Sulphones which modulate the action of gamma-secretase

ABSTRACT

Novel sulphones of Formula I are disclosed: 
                         
wherein A completes a 4-7 membered ring optionally comprising up to two heteroatoms. The compounds modulate the action of γ-secretase and are therefore useful in the treatment or prevention of Alzheimer&#39;s disease.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.10/473,727, filed Oct. 1, 2003, now abandoned which is the U.S. nationalphase of International Patent Application No. PCT/GB01/03471, filed Aug.29, 2001, which claims priority under 35 U.S.C. § 119(e) from GreatBritain Application No. 0108591.9, filed Apr. 5, 2001.

The present invention relates to a novel class of compounds, theirsalts, pharmaceutical compositions comprising them, processes for makingthem and their use in therapy of the human body. In particular, theinvention relates to novel sulphones which modulate the processing ofAPP by γ-secretase, and hence are useful in the treatment or preventionof Alzheimer's disease.

Alzheimer's disease (AD) is the most prevalent form of dementia.Although primarily a disease of the elderly, affecting up to 10% of thepopulation over the age of 65, AD also affects significant numbers ofyounger patients with a genetic predisposition. It is aneurodegenerative disorder, clinically characterized by progressive lossof memory and cognitive function, and pathologically characterized bythe deposition of extracellular proteinaceous plaques in the corticaland associative brain regions of sufferers. These plaques mainlycomprise fibrillar aggregates of β-amyloid peptide (Aβ), and althoughthe exact role of the plaques in the onset and progress of AD is notfully understood, it is generally accepted that suppressing orattenuating the secretion of Aβ is a likely means of alleviating orpreventing the condition. (See, for example, ID research alert 19961(2):1-7; ID research alert 1997 2(1):1-8; Current Opinion in CPNSInvestigational Drugs 1999 1(3):327-332; and Chemistry in Britain,January 2000, 28-31.)

Aβ is a peptide comprising 39-43 amino acid residues, formed byproteolysis of the much larger amyloid precursor protein. The amyloidprecursor protein (APP or AβPP) has a receptor-like structure with alarge ectodomain, a membrane spanning region and a short cytoplasmictail. Different isoforms of APP result from the alternative splicing ofthree exons in a single gene and have 695, 751 and 770 amino acidsrespectively.

The Aβ domain encompasses parts of both extra-cellular and transmembranedomains of APP, thus its release implies the existence of two distinctproteolytic events to generate its NH₂— and COOH-termini. At least twosecretory mechanisms exist which release APP from the membrane andgenerate the soluble, COOH-truncated forms of APP (APP_(s)). Proteaseswhich release APP and its fragments from the membrane are termed“secretases”. Most APP_(s) is released by a putative α-secretase whichcleaves within the Aβ domain (between residues Lys¹⁶ and Leu¹⁷) torelease α-APP_(s) and precludes the release of intact Aβ. A minorportion of APP_(s) is released by a β-secretase, which cleaves near theNH₂-terminus of Aβ and produces COOH-terminal fragments (CTFs) whichcontain the whole Aβ domain. Finding these fragments in theextracellular compartment suggests that another proteolytic activity(γ-secretase) exists under normal conditions which can generate theCOOH-terminus of Aβ.

It is believed that γ-secretase itself depends for its activity on thepresence of presenilin-1. In a manner that is not fully understoodpresenilin-1 appears to undergo autocleavage.

There are relatively few reports in the literature of compounds withinhibitory activity towards β- or γ-secretase, as measured in cell-basedassays. These are reviewed in the articles referenced above. Many of therelevant compounds are peptides or peptide derivatives.

Japanese Patent Publication No. 56 026847 discloses certain4-aryl-4-arylsulphonylcyclohexanone derivatives as intermediates in thesynthesis of substituted salicylic acids.

The present invention provides a novel class of non-peptidic compoundswhich are useful in the treatment or prevention of AD by modulating theprocessing of APP by the putative γ-secretase, thus arresting theproduction of Aβ.

The present invention provides a pharmaceutical composition comprising,in a pharmaceutically acceptable carrier, a compound of formula I:

wherein:

A represents the atoms necessary to complete a saturated or unsaturatedring containing 4, 5, 6 or 7 ring atoms, at most 2 of which are selectedfrom nitrogen, oxygen and sulphur, the remainder being carbon, said ringbearing, in addition to Ar² and Ar¹ SO₂, 0-3 substituents independentlyselected from ═X, halogen, CN, NO₂, N₃, R², CF₃, N(R¹)₂, OR¹, COR¹,CO₂R¹, CON(R¹)₂, OCOR¹, OCO₂R², OCON(R¹)₂, N(R¹)COR², N(R¹)CO₂R², OSO₂R²and N(R¹)SO₂R²;

X represents C(R¹)₂, CHCO₂R¹, O, S, NOR¹, CHCON(R¹)₂, NNHCOR², or theatoms necessary to complete a spiro-linked 5- or 6-membered carbocyclicor heterocyclic ring;

Ar¹ represents C₆₋₁₀aryl or heteroaryl, either of which bears 0-3substituents independently selected from halogen, CN, NO₂, CF₃, OH,OCF₃, C₁₋₄alkoxy or C₁₋₄alkyl which optionally bears a substituentselected from halogen, CN, NO₂, CF₃, OH and C₁₋₄alkoxy;

Ar² represents C₆₋₁₀aryl or heteroaryl, either of which bears 0-3substituents independently selected from halogen, CN, NO₂, CF₃, OH,OCF₃, C₁₋₄alkoxy or C₁₋₄alkyl which optionally bears a substituentselected from halogen, CN, NO₂, CF₃, OH and C₁₋₄alkoxy;

R¹ represents H or R², or two R¹ groups together with a nitrogen atom towhich they are mutually attached may complete an N-heterocyclyl groupbearing 0-3 substituents selected from ═O, ═S, ═NOR¹, halogen, CN, NO₂,R², CF₃, N(R^(1a))₂, OR¹, COR¹, CO₂R¹ and CON(R^(1a))₂;

R^(1a) represents H or R², or two R^(1a) groups together with a nitrogenatom to which they are mutually attached may complete an N-heterocyclylgroup bearing 0-3 substituents selected from ═O, ═S, halogen, C₁₋₄alkylCN, NO₂, CF₃, OH, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, carbamoyl, Ar and COAr;

R² represents C₁₋₆alkyl, C₃₋₉cycloalkyl, C₃₋₆cycloalkylC₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl or C-heterocyclyl, any of which may bear up to3 substituents independently selected from halogen, CN, NO₂, N₃, CF₃,OR^(2a), N(R^(2a))₂, CO₂R^(2a), COR^(2a), OCOR^(2a), CON(R^(2a))₂,OCON(R^(2a))₂, CONR^(2a)(OR^(2a)), CONHC(═NOH)R^(2a),CON(R^(2a))N(R^(2a))₂, heterocyclyl, phenyl and heteroaryl, saidheterocyclyl, phenyl and heteroaryl substituents themselves bearing 0-3substituents selected from halogen, CN, NO₂, CF₃, OR^(2a), N(R^(2a))₂,CO₂R^(2a), COR^(2a), CON(R^(2a))₂ and C₁₋₄alkyl; or R² represents Ar; or2 OR² groups attached to adjacent carbon atoms may complete a1,3-dioxolane ring;

R^(2a) represents H, C₁₋₆-alkyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkylC₁₋₆alkyl, C₂₋₆alkenyl, any of which optionally bears asubstituent selected from halogen, CN, NO₂, CF₃, OR^(2b), CO₂R^(2b),N(R^(2b))₂, CON(R^(2b))₂, Ar and COAr; or R^(2a) represents Ar; or twoR^(2a) groups together with a nitrogen atom to which they are mutuallyattached may complete an N-heterocyclyl group bearing 0-4 substituentsindependently selected from ═O, ═S, halogen, C₁₋₄alkyl, CN, NO₂, CF₃,OH, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, CO₂H, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, carbamoyl, Ar and COAr;

R^(2b) represents H, C₁₋₆alkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylC₁₋₆alkyl,C₂₋₆alkenyl, any of which optionally bears a substituent selected fromhalogen, CN, NO₂, CF₃, OH, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, CO₂H, amino,C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, carbamoyl, Ar and COAr; or R^(2b)represents Ar; or two R^(2b) groups together with a nitrogen atom towhich they are mutually attached may complete an N-heterocyclyl groupbearing 0-4 substituents independently selected from ═O, ═S, halogen,C₁₋₄alkyl, CN, NO₂, CF₃, OH, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, CO₂H,amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, carbamoyl, Ar and COAr;

Ar represents phenyl or heteroaryl bearing 0-3 substituents selectedfrom halogen, C₁₋₄alkyl, CN, NO₂, CF₃, OH, C₁₋₄alkoxy,C₁₋₄alkoxycarbonyl, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,carbamoyl, C₁₋₄alkylcarbamoyl and di(C₁₋₄alkyl)carbamoyl;

“heterocyclyl” at every occurrence thereof means a cyclic or polycyclicsystem of up to 10 ring atoms selected from C, N, O and S, wherein noneof the constituent rings is aromatic and wherein at least one ring atomis other than C; and

“heteroaryl” at every occurrence thereof means a cyclic or polycyclicsystem of up to 10 ring atoms selected from C, N, O and S, wherein atleast one of the constituent rings is aromatic and wherein at least onering atom of said aromatic ring is other than C;

or a pharmaceutically acceptable salt thereof.

In a subset of the compounds of formula I,

A represents the atoms necessary to complete a saturated or unsaturatedring containing 5, 6 or 7 ring atoms, at most 2 of which are selectedfrom nitrogen, oxygen and sulphur, the remainder being carbon, said ringbearing 0-3 substituents independently selected from ═C(R¹)₂, ═CHCO₂R¹,═O, ═S, ═NOR¹, halogen, CN, NO₂, N₃, R², CF₃, N(R¹)₂, OR¹, COR¹, CO₂R¹,CON(R¹)₂, OCOR¹, OCO₂R², N(R¹)COR², N(R¹)CO₂R², OSO₂R² and N(R¹)SO₂R²;

Ar¹ represents C₆₋₁₀aryl or heteroaryl, either of which bears 0-3substituents independently selected from halogen, CN, NO₂, CF₃, OH,C₁₋₄alkoxy or C₁₋₄alkyl which optionally bears a substituent selectedfrom halogen, CN, NO₂, CF₃, OH and C₁₋₄alkoxy;

Ar² represents C₆₋₁₀aryl or heteroaryl, either of which bears 0-3substituents independently selected from halogen, CN, NO₂, CF₃, OH,C₁₋₄alkoxy or C₁₋₄alkyl which optionally bears a substituent selectedfrom halogen, CN, NO₂, CF₃, OH and C₁₋₄alkoxy;

R¹ represents H or R², or two R¹ groups together with a nitrogen atom towhich they are mutually attached may complete an N-heterocyclyl groupbearing 0-3 substituents selected from ═O, ═S, ═NOR¹, halogen, CN, NO₂,R², CF₃, N(R^(1a))₂, OR¹, COR¹, CO₂R¹ and CON(R^(1a))₂;

R^(1a) represents H or R², or two R^(1a) groups together with a nitrogenatom to which they are mutually attached may complete an N-heterocyclylgroup bearing 0-3 substituents selected from ═O, ═S, halogen, C₁₋₄alkylCN, NO₂, CF₃, OH, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, carbamoyl, Ar and COAr;

R² represents C₁₋₆alkyl, C₃₋₉cycloalkyl, C₃₋₆cycloalkylC₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl or C-heterocyclyl, any of which may bear asubstituent selected from halogen, CN, NO₂, CF₃, OR^(2a), N(R^(2a))₂,CO₂R^(2a), COR^(2a), CON(R^(2a))₂, heterocyclyl, phenyl and heteroaryl,said heterocyclyl, phenyl and heteroaryl substituents themselves bearing0-3 substituents selected from halogen, CN, NO₂, CF₃, OR^(2a),N(R^(2a))₂, CO₂R^(2a), COR^(2a), CON(R^(2a))₂ and C₁₋₄alkyl, or R²represents Ar;

R^(2a) represents H, C₁₋₄alkyl, or Ar; or two R^(2a) groups togetherwith a nitrogen atom to which they are mutually attached may complete anN-heterocyclyl group bearing 0-3 substituents selected from ═O, ═S,halogen, C₁₋₄alkyl CN, NO₂, CF₃, OH, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl,amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, carbamoyl, Ar and COAr; and

Ar represents phenyl or heteroaryl bearing 0-3 substituents selectedfrom halogen, C₁₋₄alkyl, CN, NO₂, CF₃, OH, C₁₋₄alkoxy,C₁₋₄alkoxycarbonyl, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,carbamoyl, C₁₋₄alkylcarbamoyl and di(C₁₋₄alkyl)carbamoyl.

The invention further provides a compound of formula I or apharmaceutically acceptable salt thereof, with the proviso that if Arepresents —CH₂—CH(CO₂R)—CO—CH₂CH₂— or —CH═C(CO₂R)—CO—CH₂CH₂—, where Rrepresents methyl, ethyl, n-propyl or n-butyl, and Ar¹ representsphenyl, 4-methylphenyl or 4-chlorophenyl, then Ar² does not representphenyl, 4-halophenyl or 2,4-dihalophenyl where the halogens areindependently Cl or F.

Where a variable occurs more than once in formula I or in a substituentthereof, the individual occurrences of that variable are independent ofeach other, unless otherwise specified.

As used herein, the expression “C_(1-x)alkyl” where x is an integergreater than 1 refers to straight-chained and branched alkyl groupswherein the number of constituent carbon atoms is in the range 1 to x.Particular alkyl groups include methyl, ethyl, n-propyl, isopropyl andt-butyl. Derived expressions such as “C₂₋₆alkenyl”, “hydroxyC₁₋₆alkyl”,“heteroaryl”C₁₋₆alkyl, “C₂₋₆alkynyl” and “C₁₋₆alkoxy” are to beconstrued in an analogous manner.

The expression “C₃₋₉cycloalkyl” as used herein refers to nonaromaticmonocyclic or fused bicyclic hydrocarbon ring systems comprising from 3to 9 ring atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclohexenyl and bicyclo[2.2.1]heptyl.

The expression “C₃₋₆ cycloalkylC₁₋₆alkyl” as used herein includescyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl andcyclohexylmethyl.

The expression “C₆₋₁₀aryl” as used herein includes phenyl and naphthyl.

The expression “heterocyclyl” as used herein means a cyclic orpolycyclic system of up to 10 ring atoms selected from C, N, O and S,wherein none of the constituent rings is aromatic and wherein at leastone ring atom is other than carbon. Preferably not more than 3 ringatoms are other than carbon. Examples of heterocyclyl groups includeazetidinyl, pyrrolidinyl, terahydrofuryl, piperidinyl, piperazinyl,morpholinyl, thiomorpholinyl, imidazolidinyl, oxazolidinyl,thiazolidinyl, 2,5-diazabicyclo[2.2.1]heptyl,2-aza-5-oxabicyclo[2.2.1]heptyl and 1,4-dioxa-8-azaspiro[4,5]decanyl.Unless otherwise indicated, heterocyclyl groups may be bonded through aring carbon atom or a ring nitrogen atom where present. “C-heterocyclyl”indicates bonding through carbon, while “N-heterocyclyl” indicatesbonding through nitrogen.

The expression “heteroaryl” as used herein means a cyclic or polycyclicsystem of up to 10 ring atoms selected from C, N, O and S, wherein atleast one of the constituent rings is aromatic and wherein at least onering atom is other than carbon. Where a heteroaryl ring comprises two ormore atoms which are not carbon, not more than one of said atoms may beother than nitrogen. Examples of heteroaryl groups include pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furyl, thienyl,pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl,oxadiazolyl, triazolyl and thiadiazolyl groups and benzo-fused analoguesthereof. Further examples of heteroaryl groups include tetrazole,1,2,4-triazine and 1,3,5-triazine.

The term “halogen” as used herein includes fluorine, chlorine, bromineand iodine, of which fluorine and chlorine are preferred.

For use in medicine, the compounds of formula I may advantageously be inthe form of pharmaceutically acceptable salts. Other salts may, however,be useful in the preparation of the compounds of formula I or of theirpharmaceutically acceptable salts. Suitable pharmaceutically acceptablesalts of the compounds of this invention include acid addition saltswhich may, for example, be formed by mixing a solution of the compoundaccording to the invention with a solution of a pharmaceuticallyacceptable acid such as hydrochloric acid, sulphuric acid,methanesulphonic acid, fumaric acid, maleic acid, succinic acid, aceticacid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonicacid or phosphoric acid. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may include alkali metal salts, e.g. sodium or potassiumsalts; alkaline earth metal salts, e.g. calcium or magnesium salts; andsalts formed with suitable organic ligands, e.g. quaternary ammoniumsalts.

Where the compounds according to the invention have at least oneasymmetric centre, they may accordingly exist as enantiomers. Where thecompounds according to the invention possess two or more asymmetriccentres, they may additionally exist as diastereoisomers. It is to beunderstood that all such isomers and mixtures thereof in any proportionare encompassed within the scope of the present invention.

Regardless of the presence or absence of asymmetric centres, certaincompounds in accordance with the invention may exist as enantiomers byvirtue of the asymmetry of the molecule as a whole. It is to beunderstood that in such cases both enantiomers, and mixtures thereof inany proportion, are included within the scope of the invention, and thatstructural formulae depicting molecules of this type shall berepresentative of both of the possible enantiomers, unless otherwiseindicated.

In the compounds of formula I, A completes a saturated or unsaturatedring system containing 4, 5, 6 or 7 ring atoms, at most 2 of which areselected from nitrogen, oxygen or sulphur, the remainder being carbon,which optionally bears up to 3 additional substituents as definedpreviously. Preferably, A completes a 4-, 5-, 6-, or 7-membered ring inwhich at most 1 ring atom is oxygen or nitrogen and the remaindercarbon, and in certain embodiments when A completes a 4-membered ring,said ring is carbocyclic. Examples of rings completed by A includecycloheptane, cyclohexane, cyclohexene, cyclopentane, cyclopentene,cyclobutane, piperidine, pyrrolidine and pyran, with cycloheptane,cyclohexane, cyclohexene, cyclopentane, cyclopentene and pyranpreferred.

The ring completed by A may bear up to 3 substituents in addition tothose shown in formula I, but when A completes a 4-membered ring, saidring typically bears at most 2 additional substituents, preferably atmost 1 additional substituent. Where three additional substituents arepresent, two of them are preferably attached to the same ring carbonatom. Preferred substituents include ═X; halogen; azide; hydroxy oralkoxy represented by OR¹; alkylsulphonyloxy represented by OSO₂R²;amino or N-heterocyclyl represented by N(R¹)₂; optionally substitutedalkyl, alkenyl, aryl or heteroaryl represented by R²; carboxylic acid oralkoxycarbonyl represented by CO₂R¹; carbamoyl represented by CON(R¹)₂;carbamoyloxy represented by OCON(R¹)₂; and amido represented byN(R¹)COR².

When A completes a cyclobutyl ring, it is aptly substituted by OR¹.

When the ring completed by A bears one additional substituent which isconnected to the ring by a single bond, that substituent may be eithercis or trans with respect to the Ar¹SO₂ group, but the cis configurationis preferred.

Typical embodiments of ═X include alkylidene represented by ═C(R¹)₂,═CHCON(R¹)₂ or ═CHCO₂R¹; oxo represented by ═O; oximino or alkoximinorepresented by ═NOR¹; ═N—NHCOR²; or the atoms necessary to complete aspiro-linked 5- or 6-membered carbocyclic or heterocyclic ring such as:

In certain embodiments, the ring positions adjacent to the carbon bondedto the Ar¹SO₂ group are occupied by unsubstituted methylene groups.

Examples of fragments represented by A include, but are not limited to:—(CH₂)_(n)—, —(CH₂)_(p)CH═CH(CH₂)_(q)—, —(CH₂)_(r)—O—(CH₂)_(s)—,—(CH₂)_(r)—NR¹—(CH₂)_(n)—, —(CH₂)_(r)—CF₂—(CH₂)_(s)—,—(CH₂)_(r)—CR¹R²—(CH₂)_(s)—,

where n is an integer in the range 4-6;

p and q are both 0-4 such that p+q is an integer in the range 2-4;

r and s are 0-5 such that r+s is an integer in the range 2-5,

and

Y represents OR¹, N(R¹)₂, N(R¹)COR², OCOR², OCON(R¹)₂, CO₂R¹, CON(R¹)₂or CN.

Preferably, each of p, q, r and s is at least 1.

Preferably, p+q is 2 or 3, most preferably 3.

Preferably, r+s is 3 or 4, most preferably 4.

R¹ represents H or R², or two R¹ groups together with a nitrogen atom towhich they are mutually attached may complete an N-heterocyclyl group.Examples of N-heterocyclyl groups represented by N(R¹)₂ includepyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, morpholin-4-yl,thiomorpholin-4-yl and 1,4-dioxa-8-azaspiro[4,5]decan-8-yl, eachoptionally bearing up to 3 substituents as defined previously.Preferably, such heterocyclyl groups bear at most 2 substituentsselected from ═O, CF₃, OH, R², CO₂R¹ and N(R^(1a))₂.

R^(1a) represents H or R², or two R^(1a) groups together with a nitrogenatom to which they are mutually attached may complete an N-heterocyclylgroup, optionally substituted as defined previously, an example beingpiperidin-1-yl.

R² represents C₁₋₆alkyl, C₃₋₉cycloalkyl, C₃₋₆cycloalkylC₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl or C-heterocyclyl (any of which is optionallysubstituted as defined previously), or Ar. Alternatively, two OR² groupsattached to adjacent carbon atoms may complete a 1,3-dioxolane ring suchas 2,2-dimethyl-1,3-dioxolane. Preferred substituents on groupsrepresented by R² include CN, phenyl, heteroaryl (such as imidazolyl,furyl, thiazolyl, pyrazolyl, thiadiazolyl, oxadiazolyl, triazolyl,tetrazolyl and pyridyl), C-heterocyclyl (such as1-t-butoxycarbonylpyrrolidin-2-yl), COR^(2a), OR^(2a), N(R^(2a))₂,CO₂R^(2a), CON(R^(2a))₂, OCON(R^(2a))₂, CONR^(2a)(OR^(2a)), andCON(R^(2a))N(R^(2a))₂. Typically, not more than 2 substituents arepresent on R².

R^(2a) represents H, C₁₋₆alkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylC₁₋₆alkyl,C₂₋₆alkenyl, any of which optionally bears a substituent as definedpreviously; or R^(2a) represents Ar; or two R^(2a) groups together witha nitrogen atom to which they are mutually attached may complete anN-heterocyclyl group which is optionally substituted as definedpreviously. Particular values of R^(2a) include H, aryl (such asphenyl), heteroaryl (such as pyridyl), C₃₋₆cycloalkyl (such ascyclopropyl, cyclobutyl and cyclopentyl), C₃₋₆cycloalkylC₁₋₆alkyl (suchas cyclopropylmethyl), C₂₋₆alkenyl (such as allyl), and linear orbranched C₁₋₆alkyl which is optionally substituted with CF₃, Ar,OR^(2b), N(R^(2b))₂, CO₂R^(2b) or CON(R^(2b))₂.

Examples of N-heterocyclyl groups represented by N(R^(2a))₂ includepiperidin-1-yl (optionally substituted with OH, CO₂H, CO₂C₁₋₄alkyl, Meor Ph), piperazin-1-yl (optionally substituted with Me or Ph),morpholin-4-yl, thiomorpholin-4-yl, 1,1-dioxo-thiomorpholin-4-yl,2-oxo-imidazolidin-1-yl, 5,5-dimethyl-2,2-dioxo-oxazolidin-3-yl,2,5-dioxo-imidazolidin-1-yl, 2-oxo-oxazolidin-3-yl, 2-oxo-pyridin-1-yl,and 2-oxo-pyrrolidin-1-yl.

R^(2b) typically represents H or C₁₋₄alkyl.

Typically, R² represents C₂₋₆alkenyl (such as allyl) or C₁₋₆alkyl, suchas methyl, ethyl, n-propyl or t-butyl, which is optionally substitutedas described above.

Ar¹ represents C₆₋₁₀aryl or heteroaryl, either of which bears 0-3substituents independently selected from halogen, CN, NO₂, CF₃, OH,C₁₋₄alkoxy or C₁₋₄alkyl which optionally bears a substituent selectedfrom halogen, CN, NO₂, CF₃, OH and C₁₋₄alkoxy. Preferably, Ar¹represents optionally substituted phenyl or heteroaryl. Typicalheteroaryl embodiments of Ar¹ include optionally substituted pyridyl, inparticular optionally substituted 3-pyridyl. Preferably, Ar¹ bears 0-2substituents, more preferably 1 or 2 substituents, and most preferably 1substituent which is preferably in the para-position relative to thesulphone group. Typical substituents include halogen (especiallychlorine, bromine and fluorine), C₁₋₄alkyl (such as methyl), C₁₋₄alkoxy(such as methoxy), and CF₃. Examples of groups represented by Ar¹include 4-chlorophenyl, 4-bromophenyl, 4-fluorophenyl,4-trifluoromethylphenyl, 4-methylphenyl, 3,4-difluorophenyl,3,4-dichlorophenyl, 4-methoxyphenyl and 6-chloro-3-pyridyl. Mostpreferably, Ar¹ represents 4-chlorophenyl, 4-bromophenyl or4-trifluoromethylphenyl.

Ar² represents C₆₋₁₀aryl or heteroaryl bearing 0-3 substituentsindependently selected from halogen, CN, NO₂, CF₃, OH, C₁₋₄alkoxy orC₁₋₄alkyl which optionally bears a substituent selected from halogen,CN, NO₂, CF₃, OH and C₁₋₄alkoxy. Preferably, Ar² represents phenylbearing 1 or 2 substituents as indicated, and most preferably, Ar²represents 2,5-disubstituted phenyl. Preferred substituents includehalogen (especially bromine, chlorine and fluorine) and substitutedalkyl, such as hydroxymethyl. Examples of groups represented by Ar²include 2,5-dichlorophenyl, 2,5-difluorophenyl, 2-bromo-5-fluorophenyl,5-bromo-2-fluorophenyl, 5-iodo-2-fluorophenyl and2-hydroxymethyl-5-fluorophenyl. Very aptly, Ar² represents2,5-difluorophenyl.

A subclass of the compounds of the invention comprises the compounds offormula II:

and the pharmaceutically acceptable salts thereof, wherein

v is 1 and w is 0, 1 or 2, or v is 2 and w is 0 or 1;

bond a (indicated by the dotted line) may be single or double;

R³ represents H, OR¹, N(R¹)₂ or N(R¹)COR²;

R⁴ represents H, R², OR¹, OCOR², CN, CO₂R¹ or CON(R¹)₂;

and Ar¹, Ar², R¹ and R² have the same meanings as before.

When R³ represents N(R¹)₂ or N(R¹)COR², bond a is preferably single andR⁴ is preferably H.

When bond a is single, R³ may be cis or trans relative to Ar¹SO₂—, butis preferably cis.

Examples of compounds within this subclass include those wherein Ar¹represents 4-chlorophenyl, Ar² represents 2,5-difluorophenyl, v is 1 andw, a, R³ and R⁴ are as indicated in the following table:

w Bond a R³ R⁴ 0 Single H H 0 Double H H 0 Single OH H 1 Single H H 1Double H H 1 Single OH H 1 Double OH CO₂Me 1 Double O-allyl CO₂Me 1Double O—CH₂Ph CO₂Me 1 Single OH CH₂OH 1 Double OMe CO₂Me 1 Double OHCONH₂ 1 Single NH₂ H 1 Single NMe₂ H 1 Single NHCH₂Ph H 1 Singlemorpholin-4-yl H 1 Single thiomorpholin-4-yl H 1 Single NHCH₂CO₂Me H 1Single

H 1 Single

H 1 Single

H 1 Single

H 1 Single

H 1 Single

H 1 Single

H 1 Single

H 1 Single

H 1 Single

H 1 Single

H 1 Single

H 1 Single —NHCH(Me)CO₂Me H 1 Single

H 1 Single

H 1 Single

H 1 Single

H 1 Single

H 1 Single

H 1 Single

H 1 Single —NHCO(CH₂)₃NMe₂ H 1 Single

H 1 Single —NHCOCH₂NMe₂ H 1 Single —NHCOPh H 1 Single —NHCOMe H 1 SingleNHCH₂CH₂OH H 1 Single NHCH(CONH₂)CH₂CH(Me)₂ H 1 Single NHCH₂CONH₂ H 1Single OMe H 2 Double H H 2 Single H H 2 Single morpholin-4-yl H 1Single H OH 1 Single H OCOMe 1 Single H OEt 1 Single H O-allyl 1 Single—O—C(Me)₂—O— 1 Single OH OH 1 Single OCH₂CONH₂ H 1 Single OCH₂CO₂H Hand pharmaceutically acceptable salts thereof.

A subset of the compounds of formula II are those in which v is 2, bonda is single and R³ is H. Particular examples of compounds within thissubset include those in which w is 0 and Ar¹, Ar² and R⁴ have theidentities shown in the following table:

Ar¹ Ar² R⁴ 3,4-di-Cl—C₆H₃ 2,5-di-F—C₆H₃ H 4-Cl—C₆H₄ 2-F—C₆H₄ H 4-Cl—C₆H₄2,5-di-F—C₆H₃ CO₂Me 4-Cl—C₆H₄ 2,5-di-F—C₆H₃ OCOMe 4-Cl—C₆H₄2,5-di-F—C₆H₃ 1,2,3-triazol-1-yl 4-Br—C₆H₄ 2,5-di-F—C₆H₃ H 4-F—C₆H₄2,5-di-F—C₆H₃ H 4-Cl—C₆H₄ 2-Br-5-F—C₆H₃ H 4-Me—C₆H₄ 2,5-di-F—C₆H₃ H4-Cl—C₆H₄ 2,5-di-F—C₆H₃ CN 4-(CF₃O)—C₆H₄ 2,5-di-F—C₆H₃ H 3-Cl—C₆H₄2,5-di-F—C₆H₃ H 4-Cl—C₆H₄ C₆H₅ Hand pharmaceutically acceptable salts thereof.

In a further subset of the compounds of formula II, v is 2, bond a issingle, R³ is H and R⁴ is R². Within this subset, there is the group ofcompounds defined by formula IIA:

wherein m is 0 or 1;

Z represents halogen, CN, NO₂, N₃, CF₃, OR^(2a), N(R^(2a))₂, CO₂R^(2a),OCOR^(2a), COR^(2a), CON(R^(2a))₂, OCON(R^(2a))₂, CONR^(2a)(OR^(2a)),CON(R^(2a))N(R^(2a))₂, CONHC(═NOH)R^(2a), heterocyclyl, phenyl orheteroaryl, said heterocyclyl, phenyl or heteroaryl bearing 0-3substituents selected from halogen, CN, NO₂, CF₃, OR^(2a), N(R^(2a))₂,CO₂R^(2a), COR^(2a), CON(R^(2a))₂ and C₁₋₄alkyl;

R^(1b) represents H, C₁₋₄alkyl or OH;

R^(1c) represents H or C₁₋₄alkyl;

with the proviso that when m is 1, R^(1b) and R^(1c) do not bothrepresent C₁₋₄alkyl;

and Ar¹, Ar² and R^(2a) have the same meanings as before;

and the pharmaceutically acceptable salts thereof.

When m is 1 and R^(1b) is OH, Z preferably represents optionallysubstituted phenyl or heteroaryl.

In the compounds of formula IIA, Ar¹ is typically selected from phenylgroups substituted in the 4-position with halogen, methyl ortrifluoromethyl and phenyl groups substituted in the 3- and 4-positionsby halogen; and Ar² is typically selected from phenyl groups substitutedin the 2- and 5-positions by halogen. In particular embodiments, Ar¹ is4-chlorophenyl or 4-trifluoromethylphenyl and Ar² is 2,5-difluorophenyl.

R^(1b) typically represents H, methyl or OH, preferably H.

R^(1c) typically represents H or methyl, preferably H.

Z is typically selected from CN, N₃, OR^(2a), N(R^(2a))₂, CO₂R^(2a),COR^(2a), CON(R^(2a))₂, OCON(R^(2a))₂, CONR^(2a)(OR^(2a)),CON(R^(2a))N(R^(2a))₂, and optionally substituted phenyl or heteroaryl.

When Z represents OR^(2a), R^(2a) aptly represents H, Ar (especiallyheteroaryl such as pyridyl), alkyl (such as methyl, ethyl, propyl orbutyl), or substituted alkyl (especially CH₂Ar such as benzyl orpyridylmethyl).

When Z represents N(R^(2a))₂, the R^(2a) groups aptly complete anN-heterocyclyl group which is optionally substituted as described above.Preferred substituents include ═O and methyl. Specific examples ofN-heterocyclyl groups represented by Z include morpholin-4-yl,2-oxo-imidazolidin-1-yl, 5,5-dimethyl-2,2-dioxo-oxazolidin-3-yl,2,5-dioxo-imidazolidin-1-yl, 2-oxo-oxazolidin-3-yl, 2-oxo-pyridin-1-yl,and 2-oxo-pyrrolidin-1-yl.

When Z represents CO₂R^(2a), R^(2a) aptly represents H or alkyl (such asmethyl, ethyl, propyl or butyl).

When Z represents COR^(2a), R^(2a) aptly represents Ar, especiallyheteroaryl, and in particular 5-membered heteroaryl such as1,2,4-triazol-3-yl.

When Z represents CON(R^(2a))₂ or OCON(R^(2a))₂, the R^(2a) groupsindependently represent H or optionally substituted alkyl, cycloalkyl,cycloalkylalkyl or alkenyl, or together complete an N-heterocyclylgroup. Very aptly, one R^(2a) represents H and the other representsalkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,tert-butyl or 1-ethylpropyl), alkenyl (such as allyl), cycloalkyl (suchas cyclopropyl, cyclobutyl or cyclopentyl), cycloalkylalkyl (such ascyclopropylmethyl) or substituted alkyl (such as alkyl substituted withAr, especially 2-pyridylethyl, 3-(imidazol-1-yl)propyl or 2-phenylethyl;or alkyl substituted with CF₃, CO₂R^(2b), or CON(R^(2b))₂, especially2,2,2-trifluoromethyl, methoxycarbonylmethyl or carbamoylmethyl).Alternatively, the two R^(2a) groups complete an N-heterocyclyl group,such as morpholine, thiomorpholine, thiomorpholine-1,1-dioxide,4-methylpiperazine, 4-phenylpiperazine, piperidine, 4-hydroxypiperidineor piperidine which is substituted in the 3- or 4-position withCO₂R^(2b) and/or C₁₋₄alkyl, especially 3- or 4-carboxypiperidine, 3- or4-ethoxycarbonylpiperidine, 3-carboxy-3-methylpiperidine and3-ethoxycarbonyl-3-methylpiperidine.

When Z represents CONR^(2a)(OR^(2a)), each R^(2a) aptly represents H oralkyl, such as methyl.

When Z represents CON(R^(2a))N(R^(2a))₂, each R^(2a) aptly represents Hor alkyl. Specific examples include CONHNH₂ and CONHNH^(t)Bu.

When Z represents CONHC(═NOH)R^(2a), R^(2a) aptly represents alkyl suchas methyl or ethyl.

Heteroaryl groups represented by Z are very aptly 5-membered, such astetrazole, triazole, thiazole, thiadiazole, oxadiazole, pyrazole andimidazole, which are typically unsubstituted or substituted with methylor hydroxy groups. The keto-tautomers of hydroxy-substituted heteroarylgroups are to be considered interchangeable with the enol forms.Specific examples include 1,2,3,4-tetrazol-1-yl, 1,2,3,4-tetrazol-2-yl,1,2,3,4-tetrazol-5-yl, 3-hydroxy-1,2,4-triazol-5-yl, 1,2,4-triazol-3-yl,5-methyl-1,2,4-triazol-3-yl, 2,5-dimethyl-1,2,4-triazol-3-yl,1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazol-2-yl,5-methyl-1,3,4-thiadiazol-2-yl, 3-methyl-1,2,4-oxadiazol-5-yl,imidazol-2-yl, imidazol-1-yl, 4-methylthiazol-2-yl, pyrazol-1-yl,1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, and 1,2,3-triazol-2-yl.

Examples of individual compounds in accordance with formula IIA areprovided in the Examples section appended hereto.

A second subclass of the compounds of the invention comprises thecompounds of formula III:

and the pharmaceutically acceptable salts thereof, wherein

v is 1 and w is 0, 1 or 2, or v is 2 and w is 0 or 1;

X represents C(R¹)₂, CHCO₂R¹, O, NOR¹, CHCON(R¹)₂, NNHCOR², or the atomsnecessary to complete a spiro-linked 5- or 6-membered carbocyclic orheterocyclic ring;

R⁵ represents H, CO₂R¹ or CON(R¹)₂;

and R¹, R², Ar¹ and Ar² have the same meanings as before.

Preferably, v is 1 and w is 0 or 1. Most preferably, v and w are both 1.

Examples of compounds within this subclass include those wherein Ar¹represents 4-chlorophenyl, Ar² represents 2,5-difluorophenyl, v and ware both 1 and X, R¹ and R⁵ are as indicated in the following table:

═X R¹ R⁵ ═O H H ═O CH₂Ph CO₂Me ═O H CONH₂ ═O H CO₂Me ═O Me CO₂Me ═Oallyl CO₂Me ═N—OH H H ═N—OMe H H ═N—OCH₂Ph H H ═N-OCH₂CH═CH₂ H H═N—O^(t)Bu H H

H H

H H

H H ═CH₂ H H ═CHCO₂H H H

H H

H H

H H

H H

H H

N N

H N ═N—NH—COMe H H ═CHCH₂CH₂CO₂Et H H ═N—O—CH₂CO₂H H Hand the pharmaceutically acceptable salts thereof.

Further examples of compounds in accordance with formula III includethose in which R¹ and R⁵ are both H, and v, w, Ar¹, Ar² and X are asshown in the following table:

v w Ar¹ Ar² ═X 2 0 4-Cl—C₆H₄ 2,5-di-F—C₆H₃ ═O 1 2 4-Cl—C₆H₄2,5-di-F—C₆H₃ ═O 1 1 4-CF₃—C₆H₄ 2,5-di-F—C₆H₃ ═CHCO₂Et 1 0 4-Cl—C₆H₄2,5-di-F—C₆H₃

1 1 4-Cl—C₆H₄ 5-Br-2-F—C₆H₃ ═O 1 1 4-Cl—C₆H₄ 2-F-5-I—C₆H₃ ═O 1 14-MeO—C₆H₄ 2,5-di-F—C₆H₃ ═Oand the pharmaceutically acceptable salts thereof.

A third subclass of the compounds of the invention is defined by formulaIV and the pharmaceutically acceptable salts thereof:

wherein:

W represents —NR⁶—(CH₂)_(t)—, —O—CHR⁷—, or —CF₂CH₂—;

R⁶ represents R¹, COR² or CO₂R²;

R⁷ represents H or OR¹;

t is 0 or 1; and

Ar¹, Ar², R¹ and R² have the same meanings as before.

Examples of groups represented by R⁶ include H, optionally substitutedC₁₋₆alkyl (such as methyl, ethyl, benzyl and CH₂CO₂Me), C₂₋₆alkenyl(such as allyl), t-butoxycarbonyl, and acyl (such as COCH₂CH₂CO₂Me).

A fourth subclass of the compounds of the invention is defined byformula V and the pharmaceutically acceptable salts thereof:

wherein Ar¹, Ar² and R¹ have the same meanings as before.

Within this subclass, R¹ aptly represents H, C₁₋₆alkyl such as methyl,ethyl or propyl, any of which is optionally substituted with OR^(2a),CO₂R^(2a) or CON(R^(2a))₂, where R^(2a) has the same meaning as before,or C₂₋₆alkenyl such as allyl.

Individual compounds within this subclass are described in the Examplesappended hereto, in particular Examples 150-159.

and the pharmaceutically acceptable salts thereof.

It will be apparent that certain compounds of formula III are tautomersof compounds of formula II. In particular, compounds of formula IIIwherein X represents O and R¹ is H may tautomerise to correspondingcompounds of formula II wherein R³ represents OH and bond a is double.It is to be understood that both tautomeric forms are within the scopeof the invention, regardless of which tautomeric form is present in thegreater amount under any particular set of conditions.

The compounds of formula I have an activity as modulators of theprocessing of APP by γ secretase.

The invention provides pharmaceutical compositions comprising one ormore compounds of formula I or the pharmaceutically acceptable saltsthereof and a pharmaceutically acceptable carrier. Preferably thesecompositions are in unit dosage forms such as tablets, pills, capsules,powders, granules, sterile parenteral solutions or suspensions, meteredaerosol or liquid sprays, drops, ampoules, transdermal patches,auto-injector devices or suppositories; for oral, parenteral,intranasal, sublingual or rectal administration, or for administrationby inhalation or insufflation. For preparing solid compositions such astablets, the principal active ingredient is mixed with a pharmaceuticalcarrier, e.g. conventional tableting ingredients such as corn starch,lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate,dicalcium phosphate or gums or surfactants such as sorbitan monooleate,polyethylene glycol, and other pharmaceutical diluents, e.g. water, toform a solid preformulation composition containing a homogeneous mixtureof a compound of the present invention, or a pharmaceutically acceptablesalt thereof. When referring to these preformulation compositions ashomogeneous, it is meant that the active ingredient is dispersed evenlythroughout the composition so that the composition may be readilysubdivided into equally effective unit dosage forms such as tablets,pills and capsules. This solid preformulation composition is thensubdivided into unit dosage forms of the type described above containingfrom 0.1 to about 500 mg of the active ingredient of the presentinvention. Typical unit dosage forms contain from 1 to 100 mg, forexample 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient. Thetablets or pills of the novel composition can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permits theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol and cellulose acetate.

The present invention also provides a compound of formula I or apharmaceutically acceptable salt thereof for use in a method oftreatment of the human body. Preferably the treatment is for a conditionassociated with the deposition of β-amyloid. Preferably the condition isa neurological disease having associated β-amyloid deposition such asAlzheimer's disease.

The present invention further provides the use of a compound of formulaI or a pharmaceutically acceptable salt thereof in the manufacture of amedicament for treating or preventing Alzheimer's disease.

Also disclosed is a method of treatment of a subject suffering from orprone to Alzheimer's disease which comprises administering to thatsubject an effective amount of a compound according to formula I or apharmaceutically acceptable salt thereof.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, poly(vinylpyrrolidone) or gelatin.

For treating or preventing Alzheimer's Disease, a suitable dosage levelis about 0.01 to 250 mg/kg per day, preferably about 0.01 to 100 mg/kgper day, and especially about 0.01 to 10 mg/kg of body weight per day.The compounds may be administered on a regimen of 1 to 4 times per day.In some cases, however, dosage outside these limits may be used.

The compounds of formula I may be synthesised by a variety of routesstarting from the benzyl sulphones:Ar²—CH₂—SO₂—Ar¹  (1)wherein Ar¹ and Ar² have the same meanings as before. The sulphones (1)are prepared by oxidation of thioethers Ar²—CH₂—SAr¹ (2), which in turnare formed by reaction of thiols Ar¹SH (3) with benzyl derivativesAr²CH₂-L (4), where L is a leaving group such as chloride or bromide andAr¹ and Ar² have the same meanings as before. The reaction between (3)and (4) takes place in an inert solvent such as dichloromethane in thepresence of a base such as triethylamine, while the oxidation of (2) to(1) is conveniently effected by m-chloroperoxybenzoic acid, also in aninert solvent such as dichloromethane.

In a first process, bis-alkylation of (1) with L-A-L (5) (where L and Ahave the same meanings as before) provides the compounds of formula Idirectly. The reaction may be carried out in the presence of sodiumhydride in DMF at room temperature, and is particularly suitable when Arepresents a fragment such as —CH₂CH₂OCH₂CH₂—.

In a second process, sequential alkylation of (1) withL-CH₂(CH₂)_(w)CH═CH₂ and L-(CH₂)_(v)CH═CH₂ provides the bis-olefins (6)which give the cycloalkenes (7) on treatment with a rhodium catalyst:

where v, w, L, Ar¹ and Ar² have the same meanings as before. Thealkylations take place at ambient temperature in an aprotic solvent suchas DMF or THF in the presence of strong base such as sodium hydride orpotassium t-butoxide. Suitable catalysts for the cyclisation of (6) to(7) include bis(tricyclohexylphosphine)benzylidine ruthenium(IV)dichloride, the reaction taking place at room temperature in an inertsolvent such as dichloromethane.

In a third process, reaction of (1) with at least two equivalents of anacrylate ester (8) provides enols (9) which are tautomeric withketo-esters (10):

where R², Ar¹ and Ar² have the same meanings as before. On the basis ofNMR spectral data, the products are believed to exist predominantly asthe enols (9). The reaction may be carried out at ambient temperature inan inert solvent such as THF in the presence of strong base such aspotassium t-butoxide.

In a fourth process, sequential treatment of (1) with BuLi, Me₃SiCl andformaldehyde provides vinyl sulphones (11), which react with aminederivatives (12) in the presence of trifluoroacetic acid to providepyrrolidines (13):

where R², Ar¹ and Ar² have the same meanings as before. The reaction toform (11) is carried out at −78° C. in THF, while the formation of (13)may be carried out in dichloromethane at 0° C.

An alternative route to compounds of formula I involves reaction ofstyrene derivatives (27) with thiophenols Ar¹SH in the presence ofperchloric acid, with subsequent oxidation by m-chloroperoxybenzoicacid:

where A, Ar¹ and Ar² have the same meanings as before. The styrenes (27)are available by reaction of the triflates (28) with Ar²—B(OH)₂ in thepresence of a Pd(0) catalyst, and the triflates may be formed bytreatment of the ketones (29) with N-phenyl triflamide and strong basesuch as lithium di-isopropylamide at low temperatures under anhydrousconditions:

where Tf represents trifluoromethanesulphonyl and A, Ar¹ and Ar² havethe same meanings as before.

Compounds in accordance with formula I, prepared by any of the aboveprocesses, may be converted into other compounds in accordance withformula I by the application of conventional synthesis methodology.

For example, the compounds of formulae (9) or (10) may be reacted withR²-L in the presence of base to provide a mixture of O-alkyl and C-alkylderivatives (14) and (15):

where L, R², Ar¹ and Ar² have the same meanings as before. The reactionis typically carried out in refluxing acetone in the presence ofpotassium carbonate, and the products separated by conventionalchromatographic techniques.

The esters (9), (10), (14) and (15) may be hydrolysed to thecorresponding carboxylic acids, which may be coupled with amines toprovide the corresponding amides, or with alcohols to providealternative esters. Alternatively, the esters (9), (10), (14) and (15)themselves may be reacted with amines or alcohols to provide amides oralternative esters.

Reduction of the esters (9) or (10) with sodium borohydride provides thediols (16):

The cycloalkenes (7) may be reduced to the corresponding cycloalkanes(17):

where v, w, Ar¹ and Ar² have the same meanings as before. The reactionis typically carried out by hydrogenation over Pd/C at 45 psi. in asolvent such as ethyl acetate.

Alternatively, the cycloalkenes (7) may be treated sequentially withborane in THF and alkaline hydrogen peroxide to provide the alkanols(18):

where v, w, Ar¹ and Ar² have the same meanings as before. The alkanolsmay be reacted with methanesulphonyl chloride to provide thecorresponding mesylates, which may be subjected to nucleophilicdisplacement by a variety of nucleophiles such as halide, cyanide andazide (e.g. at 90° C. in DMF solution). Azides formed in this way may bereduced to the primary amines (19):

where v, w, Ar¹ and Ar² have the same meanings as before. The reductionmay be effected by treatment with triphenylphosphine in refluxingaqueous THF.

The alkanols (18) may also be oxidised to ketones (20):

where v, w, Ar¹ and Ar² have the same meanings as before. Any of theconventional oxidants may be used, such as pyridinium dichromate, but analternative route to the ketones (20) in which v and w are both 1 is bydecarboxylation of the compounds (9)/(10), which may be accomplished byheating at 150° C. in DMSO in the presence of sodium chloride and water.The latter procedure, followed by reduction of the carbonyl group withborohydride, provides an alternative route to the alkanols (18) in whichv=w=1.

The ketones (20) react with R¹—ONH₂ to form oximes and alkoximes (21):

where R¹, v, w, Ar¹ and Ar² have the same meanings as before. Thereaction may be carried out in a mixture of pyridine and ethanol at 80°C.

The ketones (20) may alternatively be converted to the amines (22) byreaction with (R¹)₂NH and sodium triacetoxyborohydride:

where R¹, v, w, Ar¹ and Ar² have the same meanings as before. Thereaction takes place at ambient temperature in dichloromethane, and isparticularly suitable for the synthesis of secondary and tertiary amineswherein at least one of the R¹ groups is other than H.

The ketones (20) may converted to the difluorides (23) by reaction with(diethylamino)sulphur trifluoride:

where v, w, Ar¹ and Ar² have the same meanings as before. The reactionmay be carried out in dichloromethane at ambient temperature.

The ketones (20) may alternatively be condensed with ylides such asPh₃P═CH(R¹)₂ and Ph₃P═CHCO₂R² to form alkylidene derivatives (24) and(25):

where v, w, R¹, R², Ar¹ and Ar² have the same meanings as before. Theylides are formed by treatment of the corresponding phosphonium bromideswith butyllithium in an aprotic solvent at low temperature, and arereacted in situ with the ketones (20).

The primary amines (19) may be alkylated and/or acylated in accordancewith standard techniques. In particular, they may be coupled with acidsR²CO₂H to form the amides (26) using any of the well known processes foramide bond formation:

where R², v, w, Ar¹ and Ar² have the same meanings as before. Suitableprocesses include conversion of the carboxylic acid to the acid chlorideprior to reaction with amine (19), and the use of coupling agents suchas dimethylaminopyridine, hydroxybenzotriazole,dicyclohexylcarbodiimide, carbonyldiimidazole and the like.

Compounds of formula IIA in which m is 0 and Z is CO₂R^(2a),CON(R^(2a))₂, CONR^(2a)(OR^(2a)), CON(R^(2a))N(R^(2a))₂ orCONHC(═NOH)R^(2a) may be prepared by coupling of a carboxylic acid (30)with (respectively) R^(2a)OH, HN(R^(2a))₂, HNR^(2a)(OR^(2a)),HN(R^(2a))N(R^(2a))₂ or H₂NC(═NOH)R^(2a),

where Ar¹, Ar², R^(1c) and R^(2a) have the same meanings as before. Anyof the standard coupling techniques may be used, including the use ofcoupling agents such as dimethylaminopyridine, hydroxybenzotriazole,dicyclohexylcarbodiimide, carbonyldiimidazole and the like. In onepreferred method, the acid is converted to the corresponding acidchloride (e.g. by treatment with oxalyl chloride in DMF solution) andreacted directly with the desired nucleophile. In another preferredmethod, the acid is converted to an active ester derivative such as thepentafluorophenol ester (e.g. by coupling with the phenol in thepresence of dicyclohexyl carbodiimide), and this intermediate is reactedwith the desired nucleophile.

The acids (30) are available by hydrolysis of the esters (31), typicallyunder alkaline conditions such as treatment with LiOH in ethanolsolution:

where Ar¹, Ar², R^(1c) and R² have the same meanings as before. In thiscontext, R² is typically methyl or ethyl.

The esters (31) are available by reduction of the alkylidene derivatives(25) in which v=w=1, optionally followed by alkylation with(C₁₋₄alkyl)-L where L is a leaving group (especially bromide or iodide)when R^(1c) is other than H. The reduction may be carried out usingsodium borohydride and nickel(II) chloride in ethanol, while theoptional alkylation may be effected by treating the ester (31,R^(1c)═H)) with strong base (e.g. sodium bis(trimethylsilyl)amide) in anaprotic solvent at low temperature, followed by treatment with(C₁₋₄alkyl)-L and warming to room temperature.

Alternatively, the unsaturated esters (25, v=w=1) may be hydrolysed tothe corresponding acids and converted to amides by reaction withHN(R^(2a))₂ prior to reduction.

Compounds of formula IIA in which m is 0 and Z is COR^(2c) may beprepared by treatment of the corresponding compounds in which Z isCONR^(2c)(OR^(2c)) with R^(2c)—Li, where R^(2c) represents R^(2a) whichis other than H. The reaction is typically carried out in an aproticsolvent at low temperature, and is particularly useful when R^(2c) inCOR^(2c) represents aryl or heteroaryl. In such cases, subsequentreduction of the carbonyl group (e.g. using sodium borohydride) providesthe compounds of formula IIA in which m is 1, R^(1b) is OH and Z is arylor heteroaryl.

Compounds of formula IIA in which m is 0 and Z is halogen, CN, N₃,OR^(2a), N(R^(2a))₂ or heteroaryl bonded through N may be obtained byreaction of a sulphonate ester (32) with (respectively) halide ion,cyanide ion, azide ion, R^(2a)OH, HN(R^(2a))₂ or heteroaryl comprisingNH in the ring:

where L¹ represents a sulphonate leaving group (such as mesylate,tosylate or triflate) and Ar¹, Ar² and R^(2a) have the same meanings asbefore. The displacement reaction may be carried out in DMF at elevatedtemperature, e.g. about 80° C. When the nucleophile is R^(2a)OH,HN(R^(2a))₂ or heteroaryl comprising NH in the ring, it is advantageousto generate the corresponding anion by treatment with sodium hydrideprior to reaction with (32).

The sulphonates (32) are prepared by reaction of the alcohols (33) withthe appropriate sulphonyl chloride (e.g. under anhydrous conditions atlow temperature in the presence of a tertiary amine).

The alcohols (33) are available from the hydroboration of alkylidenes(24) in which one of the R¹ groups is H and the other is H or C₁₋₄alkyl.The process typically involves reaction with borane in THF at roomtemperature, followed by treatment with alkaline hydrogen peroxide andseparation of the desired cis isomer by chromatography.

An alternative route to the alcohols (33) in which R^(1c) is H involvesconverting an alcohol (18) in which v=w=1 to the corresponding mesylate(or equivalent leaving group), effecting nucleophilic displacement withcyanide ion, hydrolysing the resulting nitrile to the correspondingcarboxylic acid, followed by reduction to the primary alcohol. Thehydrolysis is typically carried out under acid conditions (e.g. in amixture of acetic acid and conc. HCl at 110° C.) and the reduction isconveniently carried out by sequential treatment with isobutylchloroformate and borohydride in THF.

Compounds of formula IIA in which m is 0 and Z is OCOR^(2a) orOCON(R^(2a))₂ are available by reaction of alcohols (33) with(respectively) R^(2a)COCl or R^(2a)—NCO in accordance with standardprocedures.

Compounds of formula IIA in which m is 0 and Z represents aryl orheteroaryl bonded through C may be prepared by reaction of a sulphonylderivative (32) with the appropriate aryllithium or heteroaryllithium.Alternatively, the corresponding compounds in which Z represents afunctional group such as CN, CO₂H, CONH₂, CONHNH₂ or CONHC(═NOH)R^(2a)may be converted to heteroaryl derivatives using conventional techniquesof heterocyclic synthesis. Examples of such conversions include:

treatment of a nitrile derivative with azide to form a tetrazol-5-ylderivative;

treatment of a nitrile derivative with methanol and HCl, followed by ahydrazide, to form a 5-substituted-1,3,4-oxadiazol-3-yl derivative;

treatment of a hydrazide derivative with triethylorthoformate to form a1,3,4-oxadiazol-3-yl derivative;

treatment of a hydrazide derivative with acetamidine to form a5-methyl-1,2,4-triazol-3-yl derivative;

treatment of an amide derivative with Lawesson's reagent, followed by achloromethyl ketone, to form a 4-substituted-thiazol-2-yl derivative;

treatment of a carboxylic acid derivative (or active ester thereof) withsemicarbazide to form a 1,2,4-triazol-3-one derivative;

treatment of a carboxylic acid derivative (or active ester thereof) witha hydrazide, followed by Lawesson's reagent, to form a5-substituted-1,3,4-thiadiazol-2-yl derivative; and

treatment of a CONHC(═NOH)R^(2a) derivative with strong base (e.g.potassium t-butoxide) to form a 3-substituted-1,2,4-oxadiazol-5-ylderivative.

Illustrations of these conversions are provided in the Examples appendedhereto.

Compounds of formula IIA in which m is 1 and R^(1b) is H or C₁₋₄alkylmay be obtained via oxidation of an alcohol (33) to the correspondingaldehyde or ketone, and elaboration of the carbonyl group thereof in themanner described previously in connection with conversion of the ketones(20) into compounds of formula IIA in which m is 0.

Compounds of formula V may be obtained by treatment of the sulphones (1)with an alkyllithium (e.g. BuLi) and epichlorohydrin, and optionalalkylation of the resulting cyclobutanol with R¹-L, where R¹ and L havethe same meanings as before. The reaction of (1) with epichlorohydrin istypically carried out at low temperature in THF, and the optionalalkylation is typically effected by treatment of the cyclobutanol withsodium hydride in DME and reaction of the resulting alkoxide with R¹-L.

Where they are not themselves commercially available, the startingmaterials and reagents employed in the above-described synthetic schemesmay be obtained by the application of standard techniques of organicsynthesis to commercially available materials.

It will be appreciated that many of the above-described syntheticschemes may give rise to mixtures of stereoisomers. In particular,certain products may be formed as mixtures of cis and trans isomers inwhich a particular ring substituent is on the same or opposite side ofthe ring as the arylsulphonyl group. Such mixtures may be separated byconventional means such as fractional crystallisation and preparativechromatography.

Certain compounds according to the invention may exist as opticalisomers due to the presence of one or more chiral centres or because ofthe overall asymmetry of the molecule. Such compounds may be prepared inracemic form, or individual enantiomers may be prepared either byenantiospecific synthesis or by resolution. The novel compounds may, forexample, be resolved into their component enantiomers by standardtechniques such as preparative HPLC, or the formation of diastereomericpairs by salt formation with an optically active acid, such as(−)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaricacid, followed by fractional crystallization and regeneration of thefree base. The novel compounds may also be resolved by formation ofdiastereomeric esters or amides, followed by chromatographic separationand removal of the chiral auxiliary.

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991. The protecting groups may be removed at a convenientsubsequent stage using methods known from the art.

A typical assay which can be used to determine the level of activity ofcompounds of the present invention is as follows:

-   (1) Mouse neuroblastoma neuro 2a cells expressing human app695 are    cultured at 50-70% confluency in the presence of sterile 10 mM    sodium butyrate.-   (2) Cells are placed in 96-well plates at 30,000/well/100 μL in    minimal essential medium (MEM) (phenol red-free)+10% foetal bovine    serum (FBS), 50 mM HEPES buffer (pH7.3), 1% glutamine, 0.2 mg/ml    G418 antibiotic, 10 mM sodium butyrate.-   (3) Make dilutions of the compound plate. Dilute stock solution to    5.5% DMSO/110 μM compound. Mix compounds vigorously and store at    4° C. until use.-   (4) Add 10 μL compound/well. Mix plate briefly, and leave for 18 h    in 37° C. incubator.-   (5) Remove 90 μL of culture supernatant and dilute 1:1 with ice-cold    25 mM HEPES (pH 0.3), 0.1% BSA, 11.0 mM EDTA (+broad spectrum    protease inhibitor cocktail; pre-aliquotted into a 96-well plate).    Mix and keep on ice or freeze at −80° C.-   (6) Add back 100 μL of warm MEM+10% FBS, 50 mM HEPES (pH7.3), 1%    glutamine, 0.2 mg/ml G418, 10 mM sodium butyrate to each well, and    return plate to 37° C. incubator.-   (7) Prepare reagents necessary to determine amyloid peptide levels,    for example by ELISA assay.-   (8) To determine if compounds are cytotoxic, cell viability    following compound administration is assessed by the use of redox    dye reduction. A typical example is a combination of redox dye MTS    (Promega) and the electron coupling reagent PES. This mixture is    made up according to the manufacturer's instructions and left at    room temperature.-   (9) Quantitate amyloid beta 40 and 42 peptides using an appropriate    volume of diluted culture medium by standard ELISA techniques.-   (10) Add 15 μL/well MTS/PES solution to the cells; mix and leave at    37° C.-   (11) Read plate when the absorbance values are approximately 1.0    (mix briefly before reading to disperse the reduced formazan    product).

Alternative assays are described in Biochemistry, 2000, 39(30),8698-8704.

The Examples of the present invention all had an ED₅₀ of less than 10μM, preferably less than 1 μM and most preferably less than 100 nM in atleast one of the above assays.

The following examples illustrate the present invention.

EXAMPLES

Intermediate 1

4-Chlorothiophenol (3.6 g, 0.025 mol) in dichloromethane (100 ml) wastreated with 2,5-difluorobenzyl bromide (5.17 g, 0.025 mol) andtriethylamine (3.9 ml, 0.028 mol), reaction was stirred for 2 hours thendiluted with dichloromethane (250 ml) and washed with water (100 ml) andbrine (100 ml). The separated organic layer was dried (MgSO₄) andevaporated to dryness. Product was purified by passing down a plug ofsilica eluting with hexane-ethyl acetate mixtures. 5.12 g. ¹H NMR CDCl₃7.23 (4H,s), 6.69-6.86 (3H,m) and 4.04 (2H,s).

This thioether (5.12 g, 0.018 mol) was dissolved in dichloromethane (100ml) and treated with m-chloroperoxybenzoic acid (14.3 g, 0.042 mol (50%w/w)) and stirred for 2 hours. The reaction was then washed with Na₂S₂O₅(5% solution, 100 ml), brine (50 ml), dried (MgSO₄) and evaporated todryness. The sulphone product was purified on silica eluting withhexane-ethyl acetate mixtures, 3.6 g. ¹H NMR CDCl₃ 7.61 (2H,d, J=8.6Hz), 7.45 (2H,d, J=8.6 Hz), 7.13-7.08 (1H,m), 7.05-7.01 (1H,m),7.05-7.00 (1H,m), 6.99-6.87 (1H,m) and 4.36 (2h,s).

Intermediate 2

Intermediate 1 (500 mg, 1.66 mmol) in N,N-dimethylformamide (DMF) (2.5ml) was treated with sodium hydride (73 mg, 60% w/w in mineral oil, 1.82mmol), then allyl bromide (216 μl, 2.49 mmol). The mixture was stirredat room temperature for 16 hours, a further portion of sodium hydride(36 mg, 60% w/w in mineral oil, 0.91 mmol) added and stirring at roomtemperature continued for another 5.5 hours. The reaction mixture wasdiluted with water (40 ml) and extracted with ethyl acetate (3×50 ml),and the combined organics washed with brine (sat., 100 ml), dried(MgSO₄) and evaporated to dryness, giving an orange oil (506 mg). Thismaterial was chromatographed on silica, eluting with 0-5% ethyl acetatein hexanes to give product 199 mg. ¹H NMR (400 MHz, CDCl₃), 2.79-2.88(1H, m), 3.17-3.23 (1H, m), 4.57-4.61 (1H, m), 5.00-5.10 (2H, m),5.50-5.60 (1H, m), 6.79-6.85 (1H, m), 6.94-7.00 (1H, m), 7.23-7.28 (1H,m), 7.38-7.41 (2H, m), 7.53-7.56 (2H, m).

This mono-allyl derivative (50 mg, 0.15 mmol) in tetrahydrofuran (2 ml)was treated with allyl bromide (14 μl, 0.16 mmol). Potassiumtert-butoxide (161 μl, 1M solution in tetrahydrofuran, 0.16 mmol) wasthen dripped in slowly and mixture stirred at room temperature for 2hours. The reaction mixture was diluted with ethyl acetate (20 ml),washed with water (30 ml) and then brine (sat., 30 ml), then dried(MgSO₄) and evaporated to dryness, giving 39 mg crude material. This waspurified by preparative t.l.c., eluting with 5% ethyl acetate inhexanes, giving product 10.6 mg.

¹H NMR (400 MHz, CDCl₃), 3.08-3.15 (2H, m), 3.20-3.30 (2H, m), 5.14-5.24(4H, m), 5.75-5.90 (2H, m), 6.75-6.82 (1H, m), 6.94-7.00 (2H, m), 7.37(4H, d, J=8.0 Hz).

Intermediate 3

Intermediate 1 (1.01 g, 3.34 mmol) in DMF (3 ml) was dripped into astirring suspension of sodium hydride (134 mg, 60% w/w in mineral oil,3.34 mmol) in DMF (2 ml), and the mixture treated with 4-bromo-1-butene(508 μl, 5.01 mmol) and stirred at room temperature for 1.5 hours. Thereaction mixture was diluted with water (150 ml) and extracted withethyl acetate (3×100 ml). The combined organics were washed with brine(sat., 150 ml), dried (MgSO₄) and evaporated in vacuo to give 1.05 gcrude material which was chromatographed on silica, eluting with 0-5%ethyl acetate in hexanes to give product. 720 mg. ¹H NMR (360 MHz,CDCl₃), 1.85-1.96 (1H, m), 2.06-2.25 (2H, m), 2.49-2.58 (1H, m), 4.54(1H, dd, J=11.2 Hz and J=2.5 Hz), 4.97 (2H, dq, J=12.9 Hz and J=1.2 Hz),5.64-5.75 (1H, m), 6.80-6.86 (1H, m), 6.96-7.02 (1H, m), 7.22-7.27 (1H,m), 7.36-7.40 (2H, m), 7.51-7.55 (2H, m).

This homoallyl derivative (720 mg, 2.02 mmol) in DMF (10 ml) was drippedinto a stirring suspension of sodium hydride (202 mg, 60% w/w in mineraloil, 5.06 mmol) in DMF (7 ml). The mixture was treated with allylbromide (875 μl, 10.1 mmol) and stirred at room temperature for 64hours, then diluted with water (150 ml) and extracted with ethyl acetate(3×100 ml). The combined organics were washed with brine (sat., 200 ml),dried (MgSO₄) and evaporated in vacuo to give 910 mg crude materialwhich was chromatographed on silica, eluting with 0-5% ethyl acetate inhexanes to give product (794 mg.) A portion of this material (44 mg) wasfurther purified by preparative t.l.c., eluting with 10% ethyl acetatein hexanes to give 36 mg pure product. ¹H NMR (400 MHz, CDCl₃), 1.8-1.95(1H, m), 2.27-2.33 (1H, m), 2.41-2.46 (2H, m), 3.03 (1H, dd, J=14.8 Hzand J=7.0 Hz), 3.31 (1H, dd, J=15.4 Hz and J=6.3 Hz), 4.99-5.06 (2H, m),5.18-5.28 (2H, m), 5.73-5.84 (1H, m), 5.90-6.00 (1H, m), 6.78-6.86 (1H,m), 7.00-7.08 (2H, m), 7.31-7.37 (4H, m).

Intermediate 4

Prepared as for Intermediate 1, using 4-trifluoromethylthiophenol, andobtained as a solid. ¹H NMR (360 MHz, CDCl₃) δ 7.85-7.83 (2H, m),7.76-7.74 (2H, m), 7.15-7.10 (1H, m), 7.06-7.0 (1H, m), 6.92-6.86 (1H,m) and 4.46 (2H, s).

Intermediate 5

Prepared as for Intermediate 1, using 3,4-dichlorothiophenol, andobtained as a solid. ¹H NMR (360 MHz, CDCl₃) δ 7.76 (1H, d, J=2 Hz),7.76 (1H, d, J=8.4 Hz), 7.51-7.48 (1H, m), 7.17-7.11 (1H, m), 7.08-7.05(1H,m), 6.96-6.90 (1H, m) and 4.37 (2h, s).

Intermediate 6

Prepared as for Intermediate 1 using 4-chlorothiophenol and2-fluorobenzyl bromide as starting materials to obtain product as asolid. ¹H NMR (360 MHz, CDCl₃) δ 7.59-7.56 (2H, m), 7.44-7.41 (2H, m),7.36-7.29 (2H,m), 7.16-7.12 (1H, m), 6.95-6.90 (1H,m) and 4.40 (2H, s).

Intermediate 7

Prepared as for Intermediate 3, substituting 5-bromo-1-pentene for4-bromo-1-butene.

¹H NMR (400 MHz, CDCl₃), 1.20-1.31 (1H, m), 1.54-1.68 (1H, m), 2.06-2.12(2H, m), 2.33-2.38 (2H, m), 2.99-3.05 (1H, m), 3.28 (1H, dd, J=15.6 Hzand J=6.4 Hz), 4.97-5.05 (2H, m), 5.16-5.26 (2H, m), 5.70-5.78 (1H, m),5.87-5.98 (1H, m), 6.78-6.84 (1H, m), 6.99-7.06 (2H, m), 7.29-7.37 (4H,m).

Example 1

Intermediate 1 (1 g, 3.31 mmol) and methyl acrylate (0.84 ml, 9.27 mmol)in tetrahydrofuran (30 ml) were treated dropwise with potassium^(t)butoxide (3.64 ml 1M solution in tetrahydrofuran, 3.64 mmol). Thereaction was stirred for 2 hours, diluted with ethyl acetate (100 ml)and washed with water (50 ml) and brine (50 ml). The organic phase wasseparated, dried (MgSO₄) and evaporated to dryness, and the productpurified on silica eluting with hexane-ethyl acetate mixtures. (1.0 g).¹H NMR CDCl₃ 12.0 (1H,s), 7.41 (4H,s), 7.06-7.0 (2H,m), 6.87-6.81(1H,s), 3.81 (3H,s), 3.38 (1H,dd, J=3.2, 15.8 Hz), 3.02-2.92 (2H,m),2.52 (1H,dd, J=5.7, 18.5 Hz), 2.3-2.2 (1H,m) and 2.2-2.1 (1H,m).

Example 2

The ester from Ex. 1 (1.0 g, 2.25 mmol) in dimethylsulfoxide (10 ml) wastreated with NaCl (0.3 g, 4.96 mmol) and water (0.9 ml, 4.96 mmol) andheated at 150° C. for 2 hours. The cooled reaction mixture was dilutedwith ethyl acetate (100 ml), washed with saturated NH₄Cl (100 ml), andthe organic phase separated, dried (MgSO₄) and evaporated to dryness.The product was purified on silica eluting with hexane-ethyl acetatemixtures, 0.5 g. ¹H NMR CDCl₃ 7.43-7.37 (4H,m), 7.22-7.1 (2H,m),6.97-6.9 (1H,m), 3.05-2.98 (2H,m) and 2.61-2.53 (2H,m).

Example 3

The ketone from Ex. 2 (0.14 g, 0.36 mmol) and morpholine (0.048 ml, 0.54mmol) in dichloroethane (10 ml) were treated with sodiumtriacetoxyborohydride (0.23 g, 1.08 mmol) and stirred at roomtemperature for 18 hours. The reaction was diluted with ethyl acetate(50 ml), washed with saturated sodium bicarbonate (2×50 ml) and brine(50 ml), and the organic phase separated, dried (MgSO₄) and evaporatedto dryness. The cis and trans products were purified on silica elutingwith hexane-ethyl acetate mixtures, 0.04 and 0.06 g.

Isomer A ¹H NMR CDCl₃ 7.36-7.32 (4H,m), 7.14-7.09 (2H,m), 7.06-7.01 (1H,m), 3.75-3.73 (4H,m),2.67-2.60 (2H,m), 2.50-2.45 (4H,m), 2.36-2.32(2H,m), 2.09-2.04 (3H,m) and 1.31-1.21 (2H,m). MS (MH+) 456.

Isomer B ¹H NMR CDCl₃ 7.38-7.32 4H, m), 7.1-7.0 (2H,m), 6.87-6.80(1H,m), 3.64-3.62 (4H,m), 3.0-2.6 (2H,br m), 2.45-2.26 (4H,m), 2.32-2.04(5H,m) and 1.19-1.12 (2H,m). MS (MH+) 456.

Example 4

-   -   prepared as in example 3, substituting benzylamine for        morpholine. MS (MH+) 477(479)

Examples 5-16

To the ketone from Ex. 2 (50 mg, 0.13 mmol) in dichloroethane (2 ml) wasadded the appropriate amine (0.95 eq) and then sodiumtriacetoxyborohydride (42 mg, 0.2 mmol). The reaction was stirred atroom temperature until the starting amine was consumed (typically 24-48h), then sat. aq sodium hydrogen carbonate (1 ml) was added, followed bydilution with dichloromethane (2 ml). The organic layer was removed andtransferred to a SCX Varian Bond Elut™ cartridge and the organic layerpassed through the cartridge by suction filtration. The product wasliberated from the cartridge by passing a solution of ammonia inmethanol (2.0 M) through it. Evaporation to dryness afforded theproduct, usually as a white solid.

By this method, the following were obtained as mixtures of cis and transisomers:

Example No. —N(R¹)₂ MS (MH+)  5

438  6

467  7

529  8

510  9

510 10

468 11

468 12

467 13 —NHCH₂CO₂Me 492 14

543 15

556 16

538

Examples 17-21

The ketone from Ex. 2 (0.13 g, 0.33 mmol) and hydroxylamine oralkoxylamine H₂NOR¹ (0.92 mmol) were dissolved in pyridine-ethanol (9ml, 2:1) and heated at 80° C. for 3 hours. The reaction was then dilutedwith ethyl acetate (50 ml), washed with 2N HCl (5×25 ml), dried (MgSO₄)and evaporated to dryness. Product were purified on silica eluting withhexane-ethyl acetate mixtures.

By this route there were obtained:

Example No. R¹ 17 H 18 methyl 19 CH₂CH═CH₂ 20 t-butyl 21 benzylwith yields and spectral data as follows:

Example 17

Yield 69 mg, ¹H NMR CDCl₃ 7.60 (1H,br), 7.41-7.36 (4H, m), 7.17-7.07(2H, m), 6.93-6.87 (1H, m), 3.47-3.43 (1H,m), 2.88-2.83 (2H, m),2.31-2.23 (2H,m), 2.07-2.04 (1H,m) and 1.71-1.68 (1H,m). MS MH+ 399.

Example 18

Yield 22 mg. ¹H NMR CDCl₃ 7.41-7.39 (4H, m), 7.16-7.06 (2H, m),6.93-6.86 (1H, m), 3.76 (3H, s), 3.4-3.33 (1H, m), 2.85-2.65 (2H, m),2.55-2.52 (1H, m), 2.30-2.21 (2H, m), 2.04-2.02 (1H, m) and 1.68-1.61(1H, m).

Example 19

Yield 28 mg. ¹H NMR CDCl₃ 7.41-7.36 (4H, m), 7.15-7.05 (2H, m),6.93-6.86 (1H, m), 5.98-5.88 (1H, m), 5.27-5.16 (2H, m), 4.49-4.48 (2H,m), 3.43-3.39 (1H, m), 2.91-2.81 (2H, m), 2.57-2.34 (1H, m), 2.34-2.19(2H, m), 2.07-1.98 (1H, m) and 1.75-1.61 (1H, m).

Example 20

Yield 32 mg. ¹H NMR CDCl₃ 7.42-7.35 (1H, m), 7.18-7.05 (2H, m),6.81-6.85 (1H, m), 3.42-3.36 (1H, m), 2.82-2.76 (2H, m), 2.58-2.54 (1H,m), 2.34-2.18 (2H, m), 2.2-1.87 (1H, m), 1.7-1.62 (1H, m) and 1.21 (9JH,s).

Example 21

Yield 38 mg. ¹H NMR CDCl₃ 7.40-7.25 (9H, m), 7.15-7.05 (2H, m),6.92-6.85 (1H, m), 5.02 (2H, s), 3.45-3.41 (1H, m), 2.90-2.80 (2H, m),2.57-2.53 (1H, m), 2.32-2.16 (2H, m), 2.06-1.98 (1H, m) and 1.74-1.67(1H, m).

Example 22

The ketone from example 2, (0.1 g, 0.26 mmol) in methanol (2 ml) wastreated with NaBH₄ (0.098 g, 0.26 mmol) and stirred for 1 hour. Thereaction was quenched with HCl (1N, 10 ml), diluted with ethyl acetate(20 ml), then the organic phase was separated, dried (MgSO₄) andevaporated to dryness. The cis and trans products were purified onsilica eluting with hexane-ethyl acetate mixtures.

(a) (trans) 0.052 g. ¹H NMR CDCl₃ 7.39-7.33 (4H,m), 7.11-7.02 (2H,m),6.88-6.82 (1H,m), 3.80-3.73 (1H,m), 2.80-2.60 (2H,m), 2.22-2.16 (2H,m),2.08-2.04 (2H,m), 1.53(1H,br) and 1.27-1.13 (2H,m).

(b) (cis) ¹H NMR(CDCl₃) 7.40 (4H,s), 7.16-7.03 (2H,m), 6.90-6.83 (1H,m),3.97-3.95 (1H, m), 3.77-3.68 (1H, m), 3.51-3.49 (1H, m), 2.61-2.53(2H,m), 1.91-1.83 (2H, m) and 1.50-1.42 (2H, m).

Example 23

The ester from Ex. 1, (0.1 g, 0.22 mmol) in methanol was saturated withammonia at 0° C., sealed and stirred for 18 hours. The reaction was thenevaporated to dryness and the product purified on silica eluting withhexane-ethyl acetate mixtures, 0.056 g. ¹H NMR d₆-DMSO 7.64 (2H,d,J=8.5Hz), 7.53 (2H,d,J=8.6 Hz), 7.48-7.42 (2H,m), 7.34-7.29(1H,m), 7.19-7.10(2H,m), 3.35-3.21(2H,m), 2.85-2.76 (2H,m), 2.43-2.37 (1H,m),2.19-2.14(1H,m) and 2.0-1.95 (1H,m).

Examples 24 and 25

The product from Ex. 1 (400 mg, 0.88 mmol) and potassium carbonate (234mg, 1.66 mmol) in acetone (10 ml) were treated dropwise with methyliodide (0.28 ml, 4.4 mmol). After stirring for 72 hours at reflux andthen evaporation to dryness, the residue was partitioned between ethylacetate (3×100 ml) and water (50 ml) and brine (50 ml). The organicphase was separated, dried (MgSO₄) and evaporated to dryness. Productwas purified on silica eluting with hexane-ethyl acetate mixtures, 0.42g. A portion of this material was purified by preparative tlc, and theC-methyl product 24 [¹H NMR CDCl₃ 7.41 (2H,d, J=8.6 Hz), 7.27 (2H,d,J=10.1 Hz), 7.12-7.06 (2H,m), 6.89-6.84 (1H,m), 3.52-3.35 (1H, m), 3.22(3H,s), 2.81-2.57 (5H,m) and 1.43 (3H,s).] and the O-methyl product 25[¹H NMR CDCl₃ 7.39 (2H,d, J=8.6 Hz), 7.36 (2H,d, J=8.6 Hz), 7.12-7.08(2H,m), 6.92-6.85 (1H,m), 3.80 (3H,s), 3.59 (1H, dd, J=14.8 and 1.4 Hz),2.99-2.76 (4H,m), 2.52-2.46 (1H,m) and 1.54 (3H,s).] were obtained.

Examples 26 and 27

The product from Ex. 1 (200 mg, 0.45 mmol) in acetone (4 ml) was treatedwith potassium carbonate (125 mg, 0.90 mmol) and allyl bromide (58.7 μl,0.68 mmol). After stirring at reflux for 2.5 hours, a further portion ofallyl bromide (39 μl, 0.45 mmol) was added and stirring at refluxcontinued for a further 5 hours. The cooled reaction mixture wasevaporated in vacuo and the resulting colourless oil diluted with water(20 ml), then extracted with ethyl acetate (3×20 ml). The combinedorganics were dried (MgSO₄) then evaporated in vacuo, giving a whitefoam (230 mg) which was chromatographed on silica, eluting with 0-15%ethyl acetate in hexanes to give the C-allyl product 26 (106 mg) and theO-allyl product 27 (31 mg).

A portion of 26 (30 mg, 0.06 mmol) was purified further by preparativet.l.c., eluting with 25% ethyl acetate in hexanes to give 13.7 mg. ¹HNMR (360 MHz, CD₃OD), 2.50-2.61 (4H, m), 2.68-2.75 (2H, m), 2.85-2.95(1H, br), 3.20 (3H, s), 3.36-3.40 (1H, m), 5.11-5.17 (2H, m), 5.72-5.83(1H, m), 6.95-7.05 (1H, br), 7.20-7.25 (2H, m), 7.38-7.41 (2H, m),7.50-7.53 (2H, m).

O-allyl 27 ¹H NMR (360 MHz, CD₃OD), 2.10-2.25 (1H, m), 2.28-2.40 (1H,m), 2.71 (1H, dd, J=18.3 Hz and J=5.9 Hz), 2.98-3.02 (2H, m), 3.46 (1H,dd, J=16.4 Hz and J=3.6 Hz), 3.71 (3H, s), 4.32-4.35 (2H, m), 4.91-5.08(2H, m), 5.67-5.75 (1H, m), 6.94-7.02 (1H, m), 7.03-7.09 (1H, m),7.14-7.18 (1H, m), 7.46 (2H, dd, J=6.8 Hz and J=2.0 Hz), 7.54 (2H, dd,J=6.7 Hz and J=1.9 Hz).

Examples 28 and 29

The product from Ex. 1 (100 mg, 0.23 mmol) in acetone (2 ml) was treatedwith potassium carbonate (62 mg, 0.45 mmol) and benzyl bromide (41 μl,0.35 mmol) and stirred at reflux for 16 hours. The cooled reactionmixture was evaporated in vacuo and the resulting colourless oil dilutedwith water (20 ml), then extracted with ethyl acetate (3×20 ml). Thecombined organics were dried (MgSO₄) then evaporated in vacuo, giving awhite foam (144 mg). This material was purified by preparative t.l.c.,eluting with 25% ethyl acetate in hexanes to give the C-benzyl product28 (85 mg) ¹H NMR (360 MHz, CD₃OD), 2.30-2.40 (1H, m), 2.44-2.55 (1H,m), 2.58-2.62 (2H, m), 2.74-2.90 (2H, m), 3.10-3.14 (1H, m), 3.15 (3H,s), 3.38-3.45 (1H, m), 7.00-7.11 (1H, m), 7.18-7.30 (7H, m), 7.36 (2H,dd, J=7.0 Hz and J=1.9 Hz), 7.49 (2H, d, J=8.7 Hz)

and the O-benzyl product 29. 14 mg. ¹H NMR (360 MHz, CD₃OD), 2.02-2.18(1H, m), 2.22-2.35 (1H, m), 2.73 (1H, dd, J=18.2 Hz and J=5.7 Hz),2.90-3.02 (2H, m), 3.44 (1H, dd, J=13.2 Hz and J=2.9 Hz), 3.73 (3H, s),4.91 (2H, d, J=4.0 Hz), 6.83-6.96 (2H, m), 7.06-7.17 (6H, m), 7.43 (2H,d, J=8.6 Hz), 7.52 (2H, d, J=8.6 Hz).

Example 30

Intermediate 1 (3 g, 9.9 mmol), in tetrahydrofuran (100 ml) was treatedwith butyl lithium (6.8 ml, 10.9 mmol, 1.6M solution in hexanes) at −78°C. for 0.5 hours before adding chlorotrimethylsilane (1.4 mL, 10.9mmol), and allowing the mixture to warm to r.t. for 1 hour. The reactionwas then recooled to −78° C. and treated with further butyl lithium (7.5ml, 12 mmol, 1.6M solution in hexanes), then stirred at 0° C. for 2 hrsbefore bubbling through gaseous formaldehyde for 15 mins. The mixturewas allowed to warm to r.t. over 16 hours and was then diluted withwater and the products extracted into ethyl acetate (100 ml). Theorganic phase was separated washed with brine (50 ml), dried (MgSO₄) andevaporated to dryness. Product was purified on silica eluting withhexane-ethyl acetate mixtures, 0.49 g. ¹H NMR CDCl₃ 7.63-7.59 (2H,m),7.49-7.39 (2H,m), 7.08-6.86 (2H,m), 6.88 (1H,s) and 6.09 (1H, s).

The resulting vinyl derivative (0.05 g, 0.16 mmol), andmethoxymethyltrimethylsilylmethylbenzylamine (0.2 ml, 0.64 mmol) indichloromethane (2 ml) at 0° C. were treated with trifluoroacetic acid(0.12 mL, 0.016 mmol, 1.3M in dichloromethane) and stirred at r.t. for16 hours. The reaction was diluted with sodium hydrogen carbonate (sataq, 3 mL), the products extracted into ethyl acetate (100 ml), and theorganic phase separated, washed with brine (50 ml), dried (MgSO₄) andevaporated to dryness. Product was purified on silica eluting withhexane-ethyl acetate mixtures, 0.006 g. ¹H NMR CDCl₃ 7.49 (2H,d, J=8.6Hz), 7.38-7.18 (5H,m), 7.05-6.96 (2H,m), 6.90-6.83 (1H,m), 3.79 (1H, dd,J=11.5 and 1.0 Hz), 3.63 (2H, s), 3.14-2.89 (3H,m) and 2.58-2.50 (2H,m).

Example 31

Intermediate 2 (110 mg, 0.29 mmol) in dichloromethane (37 ml) wastreated with bis(tricylcohexylphosphine)benzylidine ruthenium (IV)dichloride (12 mg, 0.014 mmol) and the mixture stirred at roomtemperature for 16 hours, then evaporated to dryness in vacuo to give146 mg crude material. This was chromatographed on silica, eluting with0-7.5% ethyl acetate in hexanes, giving product 84 mg. ¹H NMR (400 MHz,CDCl₃), 3.10 (2H, d, J=17.3 Hz), 3.61-3.66 (2H, m), 5.65 (2H, s),6.88-6.93 (1H, m), 7.01-7.06 (2H, m), 7.38-7.41 (2H, m), 7.49-7.52 (2H,m).

Example 32

The product of Ex. 31 (74 mg, 0.21 mmol) in ethyl acetate (7 ml) wastreated with 10% palladium on carbon (20 mg) and the mixture stirredunder an atmosphere of hydrogen at 1 atm at room temperature for 19hours. The catalyst was filtered off through Hyflo™ and the solventremoved in vacuo to give 79 mg crude product. This was purified bypreparative t.l.c., eluting with 10% ethyl acetate in hexanes to providethe pure product ¹H NMR (360 MHz, CDCl₃), 1.73-1.82 (2H, m), 2.08-2.17(2H, m), 2.24-2.32 (2H, m), 2.90-2.94 (2H, m), 6.75-6.81 (1H, m),6.95-7.04 (2H, m), 7.35 (4H, s).

Example 33

The cyclopentene from Ex. 31 (104 mg, 0.29 mmol) in tetrahydrofuran (2ml) at 0° C. was treated with borane-tetrahydrofuran complex (1.0 ml,1.0M solution in tetrahydrofuran, 1.0 mmol) and the mixture was stirredfor 1 hour, warming to room temperature. A solution of hydrogen peroxide(27% w/w, 3 ml) in sodium hydroxide (4M, 3 ml) was added and stirring atroom temperature continued for 1 hour. The reaction mixture wasextracted with ethyl acetate (2×25 ml) and the combined organics werewashed with brine (sat., 30 ml), dried (MgSO₄) and evaporated in vacuoto give 116 mg crude product. This was chromatographed on silica,eluting with 30% ethyl acetate in hexanes to give product. 78 mg.

¹H NMR (400 MHz, CDCl₃), 1.75-1.84 (1H, m), 2.37-2.49 (2H, m), 2.51-2.62(1H, m), 2.88-2.96 (1H, m), 3.22-3.30 (1H, m), 4.72-4.80 (1H, m),6.74-6.82 (1H, m), 6.98-7.02 (2H, m), 7.30-7.37 (4H, m).

Example 34

Intermediate 3 (750 mg, 1.89 mmol) in dichloromethane (200 ml) wastreated with bis(tricylcohexylphosphine)benzylidine ruthenium(IV)dichloride (78 mg, 0.095 mmol) and the mixture stirred at roomtemperature for 16 hours. Evaporation to dryness in vacuo gave 750 mgmaterial which was chromatographed on silica, eluting with 5-7.5% ethylacetate in hexanes, giving product 539 mg. ¹H NMR (360 MHz, CDCl₃),1.82-1.92 (1H, br), 2.20-2.35 (2H, m), 2.80-2.92 (1H, m), 2.94-2.98 (2H,br), 5.50-5.56 (1H, m), 5.64-5.670 (1H, m), 6.75-6.88 (1H, m), 6.95-7.10(2H, m), 7.39 (4H, s).

Example 35

The cyclohexene from Example 34 (52.1 mg, 0.14 mmol) in ethyl acetate (5ml) was treated with 10% palladium on carbon (15 mg) and the mixtureshaken under an atmosphere of hydrogen at 45 psi for 1 hour. Catalystwas removed by filtration through Hyflo™ and the filtrate evaporated todryness in vacuo to give 47 mg crude material. This was purified bypreparative t.l.c., eluting with 10% ethyl acetate in hexanes to giveproduct. 43 mg. ¹H NMR (400 MHz, CDCl₃), 1.10-1.25 (2H, m), 1.26-1.40(1H, m), 1.58-1.64 (1H, m), 1.76-1.82 (2H, m), 2.04-2.12 (2H, m),2.65-2.80 (2H, br), 6.81-6.88 (1H, m), 7.01-7.11 (2H, m), 7.36 (4H, s).

Example 36

To a solution of Intermediate 1 (0.41 g, 1.36 mmol) in DMF (4 ml) wasadded sodium hydride (60% suspension in oil, 0.12 g, 3.0 mmol). Afterthe effervescence had subsided 2-bromoethyl ether (0.2 ml, 1.59 mmol)was added and the solution was stirred at room temperature for 1 h.Water (20 ml) and ethyl acetate (20 ml) were added and the organic phasewashed further with water (four times) and saturated brine. After drying(MgSO₄) and evaporating to dryness, the residue, dissolved indichloromethane, was applied to a column containing silica gel. Theproduct was eluted with 10% ethyl acetate in isohexane to give an oilwhich crystallised on treatment with diethyl ether to give the desiredproduct (0.15 g). ¹H NMR (360 MHz, CDCl₃) Λ 2.50(2H, m), 2.59(2H, broadm), 3.32(2H, t J 12 Hz), 4.02(2H, dt J 12 Hz and 3 Hz), 6.89(1H, m),7.10(2H,m), 7.38(4H, m).

Example 37

The trans cyclohexanol from Ex. 22(a) (2.7 g, 6.9 mmol) andtriethylamine (1.45 mL, 10.3 mmol) in dichloromethane (50 mL) weretreated with methane sulphonyl chloride (0.645 mL, 8.9 mmol) at −30° C.After 30 mins the mixture washed with water (20 mL), 10% aqueous citricacid (20 mL) and saturated aqueous sodium hydrogen carbonate (50 mL),dried (MgSO₄) and evaporated to dryness. The solid was triturated withether to give the mesylate (2.6 g) ¹H NMR (CDCl₃) 7.40-7.37 (4H,m),7.12-7.07 (2H,m), 6.92-6.83 (1H,m), 4.78-4.65 (1H, m), 2.96 (3H, s),2.88-2.52 (2H, m), 2.29-2.21 (4H, m) and 1.59-1.47 (2H, m).

Example 38

The mesylate from Ex. 37 (1.5 g, 3.2 mmol) in DMF (5 mL) was treatedwith sodium azide (315 mg, 4.8 mmol) and heated to 90° C. for 6 hrs. Themixture was treated with water (80 mL), and extracted with diethyl ether(3×50 mL), dried (MgSO₄) and evaporated to dryness. The solid wastriturated with ether to give the azide (1.4 g) ¹H NMR (CDCl₃) 7.40-7.34(4H,m), 7.12-7.03 (2H,m), 6.90-6.83 (1H,m), 3.78-3.76 (1H, m), 2.62-2.41(4H, m), 1.97-1.91 (2H, m) and 1.51-1.41 (2H, m).

Example 39

The azide from Ex. 38 (1 g, 2.55 mmol), dissolved in tetrahydrofuran (10mL) and water (1 mL), was treated with triphenylphosphine (740 mg, 2.8mmol) at room temperature for 15 mins and then water (5 mL) was addedand the mixture was heated at reflux for 4 hrs. The mixture was allowedto cool to r.t. and then passed through SCX Varian Bond Elut™ cartridge.The basic fraction was evaporated and a portion was purified bypreparative t.l.c. to give the primary amine. ¹H NMR (CDCl₃) 7.35(4H,s), 7.12-7.01 (2H,m), 6.88-6.81 (1H,m), 3.13-3.11 (1H, m), 2.64-2.44(4H, m), 1.78-1.68 (2H, m) and 1.52-1.39 (2H, m). MS MH+ 386(388)

Example 40

n-Butyllithium (1.6 M solution in hexanes, 15.6 mL) was added slowly toa stirred, cooled (0° C.) suspension of methyl triphenylphosphoniumbromide (9.26 g, 26.0 mmol) in tetrahydrofuran (100 mL) and the mixturewas stirred at room temperature for 3 h. The mixture was cooled to 0° C.and ketone from Ex. 2 (4 g, 10.4 mmol) in tetrahydrofuran (30 mL) wasadded. The mixture was stirred at room temperature for 1 h. then underreflux for 3 h. The mixture was cooled, poured into water and extractedwith ethyl acetate. The combined organic fractions were dried (MgSO₄)and the solvent was evaporated under reduced pressure. The residue waspurified by flash column chromatography on silica gel, eluting withisohexane:EtOAc (20:80), to give the desired product as a white solid(2.63 g, 66%). ¹H NMR (400 MHz, CDCl₃) δ 7.38 (4H, s), 7.16-7.11 (1H,m), 7.09-7.03 (1H, m), 6.91-6.84 (1H, m), 4.68-4.67 (2H, m), 2.81 (2H,br m), 2.41-2.37 (2H, m), 2.20-2.13 (2H, m), and 2.00-1.93 (2H, m).

Example 41

Prepared by the procedures of examples 1 and 2 using Intermediate 4 togive the product as a solid. (0.3 g) ¹H NMR (360 MHz, CDCl₃) δ 7.71-7.69(2H, d, J=7.5 Hz), 6.62-6.60 (2H, d, J=7.4 Hz), 7.22-7.11 (2H, m),6.95-6.88 (1H, m), 3.02-2.99 (2H, m), 2.63-2.54 (4H, m) and 2.25-2.16(2H, m).

Example 42

Intermediate 5 (0.54 g, 1.71 mM) was dissolved in tetrahydrofuran (20ml) and treated with 1,5-dibromopentane (231 μl, 1.71 mM) and ^(t)BuOKin tetrahydrofuran (3.42 mL, 1.0M solution). The reaction was leftstirring for 18 hours, then diluted with water (100 mL) and the productsextracted into ethyl acetate (3×500 mL). The combined organic phaseswere dried (MgSO₄) and evaporated to dryness. The product was purifiedon SiO₂ eluting with 2-8% ethyl acetate in isohexane to obtain pureproduct, 0.18 g. ¹H NMR (360 MHz, CDCl₃) δ 7.49-7.47 (1H, m), 7.42 (1H,d, J=2 Hz), 7.27-7.25 (1H, m), 7.13-7.04 (2H, m), 6.90-6.83 (1H, m),2.90-2.60 (2H, m), 2.12-2.04 (2H, m), 1.83-1.80 (2H, m), 1.64-1.56 (1H,m) and 1.40-1.15 (3H m).

Example 43

Prepared as for Example 42, using Intermediate 6.

¹H NMR (360 MHz, CDCl₃) δ 7.38-7.27 (6H, m), 7.14 (1H, t, J=1.3 and 7.8Hz), 6.90-6.83 (1H, m), 2.80-2.60 (2H,m), 2.14-2.04 (2H, m), 1.80-1.77(2H, m), 1.61-1.55 (1H, m) and 1.38-1.15 (3H, m).

Example 44

(1:1 mix of cis and trans)

Borane-tetrahydrofuran complex (1M in tetrahydrofuran, 2 mL, 2 mmol) wasadded to a solution of the olefin from Example 40 (383 mg, 1 mmol) intetrahydrofuran (15 mL) and the mixture was stirred at room temperaturefor 3 h. Aqueous sodium hydroxide (4M, 2.5 mL) and aqueous hydrogenperoxide (27%, 2.5 mL) were added and the mixture was stirred at roomtemperature for 2 h. Water was added and the mixture was extracted withethyl acetate. The combined organic fractions were dried (MgSO₄) and thesolvent was evaporated under reduced pressure to give the desiredproduct as a white foam (350 mg, 88%) as a 1:1 mixture of cis and transisomers. ¹H NMR (360 MHz, CDCl₃) δ 7.39-7.31 (8H, m), 7.11-7.01 (4H, m),6.88-6.81 (2H, m), 3.73 (2H, d, J=7.5 Hz), 3.35 (2H, d, J=6.2 Hz),2.42-2.30 (4H, m), 2.23-2.12 (2H, m), 1.91-1.85 (4H, m), 1.77-1.67 (4H,m), 1.51-1.45 (2H, m), 1.02-0.89 (2H, m).

Example 45

Methanesulfonyl chloride (77 μL, 0.998 mmol) was added to a solution ofthe cis and trans alcohol mixture from Example 44 (200 mg, 0.499 mmol)and triethylamine (208 μL, 1.50 mmol) in dichloromethane (10 mL) and themixture was stirred at room temperature for 24 h. The solvent wasevaporated under reduced pressure and the residue was dissolved in ethylacetate. The mixture washed with aqueous citric acid (10%), aqueoussodium hydroxide (1M), dried (MgSO₄) and the solvent was evaporatedunder reduced pressure. The residue was purified by flash columnchromatography on silica gel, eluting with isohexane:EtOAc (20:80), togive the product as a white foam (105 mg, 44%). ¹H NMR (400 MHz,DMSO-d₆) δ 7.62-7.60 (2H, m), 7.35-7.33 (3H, m), 7.21-7.09 (2H, m), 4.24(2H, d, J=7.6 Hz), 3.21 (3H, s), 2.51-2.44 (2H, m), 2.27-2.18 (2H, m),1.98-1.89 (1H, m), 1.81-1.73 (2H, m), 1.46-1.35 (2H, m).

Example 46

Morpholine (91 μL, 1.04 mmol) was added to a solution of thecis-mesylate from Example 45 (50 mg, 0.104 mmol) in acetonitrile (2 mL)and the mixture was stirred at 80° C. for 3 days. The mixture was cooledand the solvent was evaporated under reduced pressure and the residuewas dissolved in ethyl acetate. The mixture washed with aqueous sodiumhydroxide (1M), dried (MgSO₄) and the solvent was evaporated underreduced pressure. The residue was purified by flash columnchromatography on silica gel, eluting with isohexane:EtOAc (1:1), togive the product as a white foam (30 mg, 61%). ¹H NMR (360 MHz, CD₃OD) δ7.51-7.48 (2H, m), 7.44-7.38 (2H, m), 7.19-7.09 (2H, m), 7.00-6.93 (1H,m), 3.70-3.67 (4H, m), 2.56-2.24 (10H, m), 1.85-1.81 (3H, m), 1.50-1.42(2H, m).

Example 47

Ethyl(diethoxyphosphinyl)acetate (5.16 mL, 26 mmol) was added dropwiseto a slurry of sodium hydride (60% dispersion in mineral oil, 988 mg,24.7 mmol) in tetrahydrofuran (60 mL) and the mixture was stirred atroom temperature for 1 h. The ketone from Example 2 (5 g, 13 mmol) intetrahydrofuran (50 mL) was added dropwise over 20 min. and the mixturewas stirred at room temperature for 18 h. Water was added and themixture was extracted with ethyl acetate. The combined organic fractionswere washed with water, dried (MgSO₄) and the solvent was evaporatedunder reduced pressure. The residue was purified by flash columnchromatography on silica gel, eluting with isohexane:EtOAc (85:15), togive the product as a white solid (5.2 g, 88%). ¹H NMR (400 MHz, CDCl₃)δ 7.41-7.36 (4H, m), 7.18-7.13 (1H, m), 7.11-7.05 (1H, m), 6.93-6.86(1H, m), 5.64 (1H, s), 4.14-4.10 (2H, m), 3.99-3.96 (1H, m), 2.91-2.80(2H, m), 2.42-2.38 (1H, m), 2.31-2.04 (3H, m), 1.89-1.78 (1H, m),1.28-1.24 (3H, m).

Example 48

Sodium borohydride (313 mg, 8.23 mmol) was added to a mixture of theunsaturated ester from Example 47 (3.74 g, 8.23 mmol) and nickel (II)chloride (2.67 g, 20.6 mmol) in ethanol (100 mL). The mixture wasstirred at room temperature for 20 min., then water (100 mL) was added.The mixture was filtered through Hyflo™, washing with ethanol and ethylacetate. The solvent was evaporated under reduced pressure and theresidue was partitioned between ethyl acetate and water. The organiclayer was collected, dried (MgSO₄) and the solvent was evaporated underreduced pressure. The residue was purified by flash columnchromatography on silica gel, eluting with isohexane:EtOAc (85:15), togive the faster running cis-isomer, as an oil (1.36 g, 36%), ¹H NMR (400MHz, CDCl₃) δ 7.37-7.30 (4H, m), 7.09-7.00 (2H, m), 6.86-6.79 (1H, m),4.14 (2H, q, J=7.1 Hz), 2.47 (2H, d, J=7.6 Hz), 2.46-2.38 (2H, m),2.19-2.14 (1H, m), 1.76-1.71 (2H, m), 1.57-1.48 (4H, m), 1.27 (3H, t,J7.1 Hz);

and the slower running trans-isomer, as an oil (200 mg, 5.3%). ¹H NMR(400 MHz, CDCl₃) δ 7.39-7.34 (4H, m), 7.10-7.03 (2H, m), 6.88-6.82 (1H,m), 4.08 (2H, q, J=7.1 Hz), 2.98-2.85 (1H, m), 2.67-2.53 (1H, m),2.22-2.11 (2H, m), 2.06 (2H, d, J=6.9 Hz), 2.01-1.85 (3H, m), 1.20 (3H,t, J=7.1 Hz), 1.01-0.90 (2H, m).

Example 49

Lithium hydroxide (132 mg, 5.5 mmol) was added to a solution of theunsaturated ester from Example 47 (500 mg, 1.1 mmol) in ethanol (40 mL).The mixture was degassed and stirred at room temperature under nitrogengas for 24 h. The mixture was poured into aqueous hydrochloric acid (1M)and extracted with ethyl acetate. The organic extract was dried (MgSO₄)and the solvent was evaporated under reduced pressure to give theproduct as a white solid (430 mg, 92%). ¹H NMR (400 MHz, CD₃OD) δ7.53-7.51 (2H, m), 7.45-7.39 (2H, m), 7.27-7.18 (2H, m), 7.07-7.00 (1H,m), 5.67 (1H, s), 3.97-3.93 (1H, m), 2.96-2.90 (2H, m), 2.47-2.43 (1H,m), 2.26-2.09 (3H, m), 1.84-1.77 (1H, m).

Example 50

Lithium hydroxide (350 mg, 14.57 mmol) was added to a solution of thecis-ester from Example 48, (1.33 g, 2.91 mmol) in ethanol (40 mL). Themixture was degassed and stirred at room temperature under nitrogen gasfor 5 h. The mixture was poured into aqueous hydrochloric acid (1M) andextracted with ethyl acetate. The organic extract was dried (MgSO₄) andthe solvent was evaporated under reduced pressure to give a white solidwhich was then crystallized from IPA to give the product as a whitesolid (950 mg, 76%). ¹H NMR (400 MHz, CD₃OD) δ 7.51-7.49 (2H, m),7.40-7.37 (2H, m), 7.19-7.10 (2H, m), 7.00-6.94 (1H, m), 2.51-2.35 (6H,m), 2.13-2.10 (1H, m), 1.78-1.74 (2H, m), 1.57-1.50 (2H, m).

Example 51

The acid from Example 50 (50 mg, 0.117 mmol), morpholine (30 μL, 0.351mmol), 1-hydroxybenzotriazole (24 mg, 0.176 mmol) and triethylamine (65μL, 0.468 mmol) was stirred in tetrahydrofuran at room temperature undernitrogen gas for 10 min. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (45 mg, 0.234 mmol) was added to the mixture and stirredfor 24 h. The mixture was poured into aqueous sodium hydroxide (1M) andextracted with ethyl acetate. The organic extract was dried (MgSO₄) andthe solvent was evaporated under reduced pressure. The residue waspurified by flash column chromatography on silica gel, eluting with 5 to10% methanol in dichloromethane, to give the product as a white foam (50mg, 86%).

¹H NMR (400 MHz, CD₃OD) δ 7.50 (2H, d, J=8.6 Hz), 7.37 (2H, d, J=8.6Hz), 7.19-7.09 (2H, m), 7.00-6.93 (1H, m), 3.69-3.63 (4H, m), 3.59-3.56(4H, m), 2.55 (2H, d, J=7.4 Hz), 2.47-2.39 (4H, m), 2.16-2.07 (1H, m),1.78-1.74 (2H, m), 1.58-1.51 (2H, m). m/z (ES⁺) (M+1) 498+500.

Examples 52-63

The following compounds were prepared according to the method of Example51, using the appropriate amine in place of morpholine.

m/z (ES⁺) Ex. —NR₂ Formula M.W. (M + 1) 52

C₂₅H₂₉ClF₂N₂O₃S 510 512 511 513 53

C₃₀H₃₁ClF₂N₂O₃S 572 574 573 575 54

C₂₅H₂₈ClF₂NO₄S 511 513 512 514 55

C₂₇H₂₇ClF₂N₂O₃S 532 534 533 535 56

C₂₆H₂₈ClF₂N₃O₃S 535 537 536 538 57

C₂₈H₃₂ClF₂NO₅S 567 569 568 570 58

C₂₈H₃₂ClF₂NO₅S 567 569 568 570 59

C₂₈H₃₂ClF₂NO₅S 567 569 568 570 60

C₂₈H₃₂ClF₂NO₅S 567 569 568 570 61

C₂₅H₂₈ClF₂NO₃S 495 497 496 498 62

C₂₉H₃₄ClF₂NO₅S 581 583 582 584 63

C₂₉H₃₄ClF₂NO₅S 581 583 582 584

Example 64

Lithium hydroxide (20 mg, 0.833 mmol) was added to a solution of Example57 (95 mg, 0.167 mmol) in ethanol (12 ml) and water (4 ml). The mixturewas degassed and stirred at room temperature under nitrogen gas for 18h. The mixture was poured into aqueous hydrochloric acid (1M) andextracted with ethyl acetate. The organic extract was dried (MgSO₄) andthe solvent was evaporated under reduced pressure to give the product asa white solid (75 mg, 83%). ¹H NMR (400 MHz, CD₃OD) δ 7.50 (2H, d, J=8.6Hz), 7.38 (2H, d, J=8.6 Hz), 7.19-7.10 (2H, m), 7.00-6.93 (1H, m),4.37-4.32 (1H, m), 3.98-3.90 (1H, m), 3.26-3.18 (1H, m), 2.90-2.82 (1H,m), 2.64-2.38 (7H, m), 2.10-2.06 (1H, m), 2.00-1.91 (2H, m), 1.78-1.49(6H, m). m/z (ES⁺) (M+1) 540+542.

Examples 65-69

The following compounds were prepared according to the method of Example64 using the appropriate esters from Examples 58-63.

m/z (ES⁺) Ex. —NR₂ Formula M.W (M + 1) 65

C₂₆H₂₈ClF₂NO₅S 539 541 540 542 66

C₂₈H₃₂ClF₂NO₅S 539 541 540 542 67

C₂₈H₃₂ClF₂NO₅S 539 541 540 542 68

C₂₇H₃₀ClF₂NO₅S 553 555 554 556 69

C₂₇H₃₀ClF₂NO₅S 553 555 554 556

Example 70

The acid from Example 49 (30 mg, 0.0703 mmol) was coupled withmorpholine (18.4 μL, 0.211 mmol) following the procedure of Example 51to give the product as a white foam (30 mg, 86%). ¹H NMR (400 MHz,CD₃OD) δ 7.53-7.51 (2H, d, m), 7.45-7.41 (2H, d, m), 7.26-7.19 (2H, m),7.07-7.00 (1H, m), 5.88 (1H, s), 3.64-3.58 (6H, m), 3.51-3.49 (2H, m),2.98-2.92 (3H, m), 2.48-2.44 (1H, m), 2.23-2.06 (3H, m), 1.87-1.80 (1H,m).

Example 71

Prepared from the acid from Example 49 and 4-hydroxypiperidine accordingto the method of Example 51. ¹H NMR (400 MHz, CD₃OD) δ 7.54-7.51 (2H,m), 7.43-7.41 (2H, m), 7.25-7.19 (2H, m), 7.07-7.00 (1H, m), 5.88 (1H,s), 4.12-4.02 (1H, m), 3.86-3.76 (2H, m), 3.26-3.12 (2H, m), 3.00-2.83(3H, m), 2.48-2.44 (1H, m), 2.23-2.05 (3H, m), 1.87-1.78 (3H, m),1.43-1.40 (2H, m).

Example 72

Prepared from the acid from Example 49 (30 mg, 0.0703 mmol) and1-methylpiperazine (23 μL, 0.211 mmol) by the method of Example 51 togive the product as a white foam (25 mg, 70%). ¹H NMR (400 MHz, CD₃OD) δ7.53-7.51 (2H, m), 7.44-7.41 (2H, m), 7.25-7.19 (2H, m), 7.07-7.00 (1H,m), 5.88 (1H, s), 3.66-3.60 (2H, m), 3.53-3.48 (2H, m), 2.93-2.89 (3H,m), 2.48-2.39 (5H, m), 2.30 (3H, s), 2.23-2.08 (3H, m), 1.86-1.80 (1H,m). m/z (ES⁺) (M+1) 509+511.

Examples 73-75

The following compounds were prepared according to the method of Example70, using the appropriate amine in place of morpholine.

m/z (ES⁺) (M + Ex. —NR₂ Formula M.W. 1) 73

C₃₀H₂₉ClF₂N₂O₃S 570 572 571 573 74

C₂₇H₂₅ClF₂N₂O₃S 530 532 531 533 75

C₂₆H₂₆ClF₂N₃O₃S 533 535 534 536

Examples 76-86

The following were prepared as mixtures of cis and trans isomers by theprocedure outlined for Examples 5-16:

Example No —NR₂ MS (MH+) 76

549 77

599 78

561 79

567 80

561 81

429 82

476 83

476 84

476 85

471 86

499In the case of Examples 81-86, the cis and trans isomers were separatedby flash chromatography using ethyl acetate/methanol mixtures.

Example 87

The cis alcohol from Example 22(b) (100 mg, 0.26 mmol) in dry THF wastreated with NaH (60% dispersion, 16 mg, 0.39 mmol) and methyl iodide(0.2 ml, excess) and heated in a sealed tube at 70° C. for 18 h. Thereaction was quenched with sat. aq. ammonium chloride and the productsextracted with ethyl acetate (3×20 ml). The organics were washed withbrine, dried (MgSO₄), filtered and evaporated. The crude oil waspurified by flash chromatography eluting with 2:1 ^(i)hexane/ethylacetate to give 35 mg of product.

¹H NMR δ (ppm) (CDCl₃): 1.26 (3 H, t, J=7.0 Hz), 1.99 (2 H, s), 2.04 (1H, s), 2.48 (3 H, d, J=0.7 Hz), 3.26-3.32 (3 H, m), 6.82-6.90 (1 H, m),7.01-7.13 (2H, m), 7.37 (4 H, s).

Example 88

The cis alcohol from Example 22(b) (100 mg, 0.26 mmol) in dry DCM (5 ml)under nitrogen was treated with triethylamine (53 mg, 0.52 mmol) andacetyl chloride (41 mg, 0.52 mmol) using catalytic DMAP. The reactionwas stirred at room temperature for 12 h. Reaction was diluted with DCM,washed with water, brine, dried (MgSO₄), filtered and evaporated. Thecrude oil was purified by flash chromatography eluting with 1:1^(i)hexane/ethyl acetate) to give 45 mg of product. ¹H NMR δ (ppm)(CDCl₃): 1.24 (1 H, d, J=6.3 Hz), 1.42 (2 H, t, J=14.7 Hz), 1.97 (1 H,s), 2.03 (1 H, d, J=10.9 Hz), 2.11 (3 H, s), 2.53 (3H, d, J=11.6 Hz),4.88-4.91 (1 H, m), 6.82-6.89 (1 H, m), 7.03-7.12 (2 H, m), 7.35-7.37(4H, m)

Example 89

The ketone from Example 2 (200 mg, 0.52 mmol) in dry toluene (7 ml) wastreated with ethanediol (0.1 ml, 1.56 mmol), p-toluenesulfonic acid (10mg) and 4A molecular sieves (30 mg). The mixture was heated at refluxfor 18 h. The reaction was neutralised with solid NaHCO₃, filtered andevaporated. The residue was dissolved in DCM, washed with aqueousNaHCO₃, dried (MgSO₄), filtered and evaporated. The crude oil waspurified by flash chromatography (SiO₂, 2:1 ^(i)hexane/ethyl acetate to1:1) to give the product (65 mg).

¹H NMR δ (ppm) (CDCl₃): 1.24 (1 H, d, J=6.3 Hz), 1.42 (2 H, t, J=14.7Hz), 1.97 (1 H, s), 2.03 (1 H, d, J=10.9 Hz), 2.11 (3 H, s), 2.53 (3H,d, J=11.6 Hz), 4.88-4.91 (1 H, m), 6.82-6.89 (1 H, m), 7.03-7.12 (2 H,m), 7.35-7.37 (4H, m)

Example 90

The cis amino-ester from Example 13 (100 mg, 0.23 mmol) (obtained byflash chromatography of the cis/trans mixture using ethylacetate/methanol) was treated with a 2.0M solution of ammonia inmethanol (3 ml). The solution was heated in a sealed tube for 18 hours,the reaction concentrated and the residue purified by flashchromatography (SiO₂, ethyl acetate to 3:1 ethyl acetate/methanol togive 70 mg. product amide. ¹H NMR δ (ppm) (CDCl₃): 1.41-1.49 (2 H, m),1.79-1.83 (2 H, m), 2.42-2.58 (4 H, m), 2.76 (1 H, t, J=3.1 Hz), 3.28 (2H, s), 5.43-5.47 (1 H, m), 6.81-6.88 (1 H, m), 6.98-7.11 (2H, m),7.32-7.38 (4H, m).

Example 91

Prepared from Intermediate 7 (2.10 g, 5.12 mmol), using the method ofExample 34. Yield 2.00 g. ¹H NMR (400 MHz, CDCl₃), 1.28-1.35 (1H, m),1.81-1.87 (1H, m), 2.14-2.18 (2H, m), 2.30-2.37 (1H, m), 2.86-2.90 (1H,m), 3.04-3.07 (1H, m), 3.30-3.36 (1H, m), 5.63-5.68 (1H, m), 5.79-5.84(1H, m), 6.81-6.87 (1H, m), 6.92-7.04 (2H, m), 7.37 (4H, s).

Example 92

The product of Example 91 (57.8 mg, 0.151 mmol) in ethyl acetate (5 ml)was hydrogenated by the method of Example 35 to give the cycloheptane(46 mg). ¹H NMR (400 MHz, CDCl₃), 1.38-1.46 (4H, m), 1.51-1.60 (2H, m),1.84-1.92 (2H, m), 2.32-2.39 (2H, m), 2.67-2.72 (2H, m), 6.85-6.91 (1H,m), 6.98-7.06 (2H, m), 7.33-7.38 (4H, m).

Example 93

The cyclohexene from Example 34 (352 mg, 0.957 mmol) in tetrahydrofuran(6 ml) was treated with borane-tetrahydrofuran complex (1M intetrahydrofuran, 4.8 ml, 4.78 mmol) at 0° C. Hydrogen peroxide (27% w/win water, 10 ml) was mixed with sodium hydroxide solution (4N, 10 ml),then added slowly to the reaction and stirring continued for a furtherhour at room temperature. The reaction mixture was extracted with ethylacetate (2×100 ml), and the combined organics washed with brine (sat.,100 ml), dried (MgSO₄) and evaporated in vacuo to give 415 mg mixture of4 isomers. The isomers were separated by chromatography on silica,eluting with 30-50% ethyl acetate in hexanes. Fractions rich in3-hydroxy isomers (198 mg) were purified by preparative t.l.c, elutingwith 30% ethyl acetate in hexanes followed by two crystallisations fromdiethyl ether in hexanes to give the cis-3-alcohol product. 1.9 mg. ¹HNMR (400 MHz, CDCl₃), 1.23-1.39 (2H, m), 1.89-2.09 (4H, m), 2.55-3.10(2H, br), 3.48-3.54 (1H, m), 6.82-6.89 (1H, m), 7.02-7.25 (2H, m),7.35-7.40 (4H, m).

Example 94

A mixture of cis-3- and cis-4-alcohols (2.52 g, 6.53 mmol) (from Example93) in dichloromethane (80 ml) at 0° C. was treated with triethylamine(1.36 ml, 9.79 mmol) then methansulfonyl chloride (603 μl, 7.83 mmol).The mixture was stirred for 3.5 hours, slowly warming to roomtemperature, then washed with water (200 ml), citric acid (10% aq., 200ml) and sodium hydrogen carbonate (sat. aq., 200 ml), dried (MgSO₄) andevaporated in vacuo to give 2.97 g mixture of 2 isomers. Isomers wereseparated by chromatography on silica, eluting with 100% dichloromethanegiving cis-3-mesylate (182 mg), cis-4 mesylate (185 mg) and mixedfractions (2.19 g). Cis-3-mesylate (52 mg) was purified by preparativet.l.c., eluting with 100% dichloromethane to give product. 48 mg. ¹H NMR(400 MHz, CDCl₃), 1.24-1.31 (1H, m), 1.63 (1H, dq, J=4.4 Hz and J=12.4Hz), 1.96-2.20 (3H, br), 2.31 (1H, dt, J=2.4 Hz and J=12.4 Hz),2.50-2.90 (1H, br), 3.01 (3H, s), 3.10-3.25 (1H, br), 4.40-4.54 (1H, m),6.88-6.93 (1H, m), 7.07-7.11 (2H, m), 7.34-7.41 (4H, m).

Example 95

The cis-4-mesylate fraction from Example 94 (46 mg) was purified bypreparative t.l.c., eluting with 100% dichloromethane to give product.31 mg. ¹H NMR (400 MHz, CDCl₃), 1.40-1.10 (2H, br), 2.15-2.25 (2H, br),2.50-2.60 (4H, br), 3.08 (3H, s), 4.89 (1H, t, J=2.8 Hz), 6.80-6.90 (1H,m), 7.06-7.10 (2H, m), 7.33-7.40 (4H, m).

Example 96

Cis-3-mesylate from Example 94 (66 mg, 0.142 mmol) inN,N-dimethylformamide (2 ml) was treated with sodium azide (14 mg, 0.213mmol) and the mixture heated to 95° C. for 16 hours. A further portionof sodium azide (9 mg, 0.142 mmol) was added and stirring at 95° C.continued for a further 24 hours. The reaction was diluted with water(40 ml), extracted with 20% ethyl acetate in diethyl ether (3×60 ml) andthe combined organics washed with brine (sat., 100 ml), dried (MgSO₄)and evaporated in vacuo to give 46 mg crude product. This was purifiedby chromatography on silica, eluting with 15% ethyl acetate in hexanesto give 12 mg product which was further purified by preparative t.l.c.,eluting with 15% ethyl acetate in hexanes to give pure product. 7.2 mg.¹H NMR (400 MHz, CDCl₃), 1.62-1.71 (2H, m), 1.82-1.95 (2H, m), 2.30-2.50(2H, br), 2.65-2.82 (2H, br), 4.18-4.23 (1H, m), 6.79-6.86 (1H, m),6.70-7.04 (2H, m), 2.28-2.38 (4H, m).

Example 97

A mixture of cis-3- and trans-3-alcohols (650 mg, 1.68 mmol, isomerratio 3:1) (from Example 93) in dichloromethane (20 ml) was treated withacetic anhydride (159 μl, 1.68 mmol) and dimethylaminopyridine (21 mg,0.168 mmol). After 1 hour stirring at room temperature, the reaction wasquenched with water (30 ml), washed with citric acid (10% aq., 30 ml)then sodium hydrogen carbonate (sat., aq., 30 ml). The organics weredried (MgSO₄) and evaporated in vacuo to give 843 mg mixture of isomers.Separation by chromatography on silica, eluting with 15-20% ethylacetate in hexanes, gave the cis-isomer (209 mg). ¹H NMR (360 MHz,CDCl₃), 1.20-1.50 (2H, br), 1.90-2.00 (2H, br), 2.05 (3H, s), 2.05-2.20(2H, br), 2.50-3.05 (2H, br), 4.54-4.60 (1H, br), 6.82-6.90 (1H, m),7.02-7.08 (2H, m), 7.33-7.39 (4H, m).

Example 98

The trans-acetate fraction from Example 97 (220 mg) was purified bychromatography on silica, eluting with 100% dichloromethane, then 20%ethyl acetate in hexanes to give 90 mg material which was furtherpurified by preparative t.l.c., eluting with 5% ethyl acetate indichloromethane to give product. 49 mg. ¹H NMR (400 MHz, CDCl₃),1.55-1.88 (3H, m), 2.09 (3H, s), 2.28-2.36 (1H, m), 2.49-2.54 (1H, m),2.58-2.65 (1H, br), 2.92-3.04 (2H, m), 5.40-5.44 (1H, m), 6.79-6.84 (1H,m), 7.01-7.07 (2H, m), 7.31-7.38 (4H, m).

Example 99

A degassed solution of trans-3-acetate from Example 98 (44 mg, 0.103mmol) in methanol/water/tetrahydrofuran (3:1:1, 2 ml) was treated withlithium hydroxide (12 mg, 0.50 mmol). After 1 hour stirring at roomtemperature, a further portion of lithium hydroxide (12 mg, 0.50 mmol)was added, and after stirring at room temperature for 16 hours, thereaction was heated to 75° C. for 4 hours, cooled, diluted with water(10 ml), acidified with hydrochloric acid (1N, 3 ml), then extractedwith ethyl acetate (3×20 ml). The combined organics were washed withbrine (sat., 70 ml), dried (MgSO₄) and evaporated to give 35 mg crudeproduct. This was purified by preparative t.l.c., eluting with 30% ethylacetate in hexanes to give product. 11.3 mg. ¹H NMR (400 MHz, CDCl₃),1.63-1.84 (4H, m), 2.31-2.36 (1H, br), 2.45-2.57 (2H, br), 2.84-2.92(1H, br), 4.37-4.45 (1H, br), 6.77-6.84 (1H, m), 6.97-7.05 (2H, m),7.29-7.38 (4H, m).

Example 100

Cis-3-alcohol (Example 93) (49 mg, 0.128 mmol) in tetrahydrofuran (2 ml)was dripped into a stirring suspension of sodium hydride (5.6 mg, 60%w/w in mineral oil, 0.140 mmol) in tetrahydrofuran (1 ml) and themixture heated to reflux for 2 hours. After cooling to 0° C.,bromoethane (38 μl, 0.512 mmol) was added, the mixture stirred at roomtemperature for 16 hours, then further portions of sodium hydride (11mg, 60% w/w in mineral oil, 0.256 mmol) and bromoethane (29 μl, 0.384mmol) were added. After stirring at reflux for 24 hours, the reactionwas cooled to room temperature, acidified with hydrochloric acid (2N, 2ml) and extracted with diethyl ether (3×20 ml). The combined organicswere washed with brine (sat., 50 ml), dried (MgSO₄) and evaporated togive 86 mg crude product. This was purified by preparative t.l.c.,eluting with 30% ethyl acetate in hexanes to give product. 10 mg. ¹H NMR(360 MHz, CDCl₃), 1.15-1.35 (6H, m), 1.87-2.04 (4H, m), 2.50-2.80 (1H,br), 3.06-3.20 (1H, br), 3.42-3.56 (2H, m), 6.84-6.91 (1H, m), 7.02-7.15(2H, m), 7.39 (4H, s).

Example 101

Prepared by the method of Example 100, substituting allyl bromide forbromoethane. The crude product was purified by preparative t.l.c.,eluting with 15% ethyl acetate in hexanes to give product. 23 mg. ¹H NMR(360 MHz, CDCl₃), 1.15-1.40 (3H, m), 1.85-2.02 (4H, m), 2.50-3.00 (1H,br), 3.12-3.24 (1H, br), 3.98-4.00 (2H, m), 5.14-5.26 (2H, m), 5.82-5.95(1H, m), 6.84-6.90 (1H, m), 7.03-7.08 (2H, m), 7.40 (4H, s).

Example 102

The amine from Example 39 (50 mg, 0.13 mmol) was dissolved indichloromethane (1 mL) and was treated with triethylamine (27 μL, 0.2mmol) and then acetic anhydride (18 μL, 0.2 mmol) and the mixture wasstirred at r.t. for 24 hrs. The mixture was diluted with water (2 mL)and separated on a Bond Elut™ cartridge before purifying by preparativet.l.c to give the amide. ¹H NMR (CDCl₃) 7.36 (2H, d, J=8.6 Hz), 7.29(2H, d, J=9.3 Hz), 7.08-7.03 (2H,m), 6.88-6.83 (1H,m), 5.98-5.96 (1H,m), 4.04-4.01 (1H, m), 2.58-2.50 (2H, m), 2.41-2.34 (2H, m), 2.04 (3H,s), 1.97-1.91 (2H, m) and 1.54-1.46 (2H, m).

Example 103

The amine from Example 39 (50 mg, 0.13 mmol) was dissolved indichloromethane (1 mL) and was treated with triethylamine (54 μL, 0.4mmol), benzoic acid (21 mg, 0.17 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (32 mg, 0.17mmol) and the mixture was stirred at r.t. for 24 hrs. The mixture wasdiluted with water (2 mL) and separated on a Bond Elut™ cartridge beforepurifying by preparative t.l.c to give the amide. ¹H NMR (CDCl₃)7.77-7.72 (2H, m), 7.69-7.45 (3H, m), 7.39 (2H, d, J=11.2 Hz), 7.31 (2H,d, J=11.8 Hz), 7.26-7.03 (2H, m), 6.90-6.83 (1H, m), 6.43-6.40 (1H, m),4.24-4.20 (1H, m), 2.63-2.58 (2H, m), 2.48-2.41 (2H, m), 2.12-2.07 (2H,m) and 1.68-1.54 (2H, m).

Example 104-107

Using the method of Example 103, the following were prepared:

Example R MS (MH+) 104 Dimethylaminomethyl 470 (472) 1052-(piperidin-1-yl)ethyl 525 (527) 106 3-(dimethylamino)propyl 499 (501)107 (1H-imidazol-5-yl)methyl 493 (495)

Example 108

The amine from Example 39 (50 mg, 0.13 mmol) was dissolved in methanol(1 mL) and was treated with alumina (50 mg) and furfuraldehyde (2.5 μL,0.26 mmol) and the mixture was stirred at r.t. for 16 hrs. Sodiumborohydride was then added and the mixture was stirred for a further 16hrs. The mixture was separated on a SCX Varian Bond Elut™ cartridgebefore purifying the basic fraction by preparative t.l.c to give theproduct. ¹H NMR (CDCl₃) 7.38-7.32 (4H, m), 7.11-7.00 (2H, m), 6.87-6.80(1H,m), 6.29 (1H, dd, J=2.8 and 1.6 Hz), 6.13 (1H, d, J=2.8 Hz), 3.76(2H, s), 2.76-2.73 (1H, m), 2.64-2.56 (2H, m), 2.46-2.38 (2H, m),1.82-1.76 (2H, m) and 1.41-1.34 (2H, m); MS MH+ 465(467).

Example 109

Prepared as in Example 108, substituting 4(5)-imidazolecarboxaldehydefor furfural. MS MH+ 465(467).

Example 110

The amine from Example 39 (50 mg, 0.13 mmol) was dissolved indichloroethane (1 mL) and treated with N-benzoyl-4-piperidone (53 mg,0.26 mmol) and sodium triacetoxyborohydride (55 mg, 0.26 mmol) and themixture was stirred at r.t. for 16 hrs. The mixture was diluted withsaturated aqueous sodium bicarbonate (1 mL) and was separated on a BondElut™ cartridge before passing through a SCX Bond Elut™ cartridge. Thebasic fraction was purified by preparative t.l.c to give the amide.

¹H NMR (CDCl₃) 7.41-7.30 (9H, m), 7.10-7.01 (2H, m), 6.87-6.80 (1H,m),4.62-4.50 (1H,m), 3.78-3.71 (1H, m), 3.08-2.91 (3H, m), 2.79-2.72 (1H,m), 2.61-2.43 (4H, m), 2.03-1.75 (4H, m) and 1.44-1.24 (4H, m); MS MH+573(575).

Example 111

The cyclopentene from Example 31 (296 mg, 0.84 mmol) was dissolved indichloromethane (40 mL), methanol (40 mL) and was stirred at −78° C. andpurged with oxygen over 5 mins followed by bubbling through ozone untilthe blue colour persisted. The solution was then re-purged with oxygenand treated with sodium borohydride (316 mg, 8.4 mmol), and allowed towarm to r.t. over 16 hrs. The solvent was removed in vacuo and theresidue was partitioned between ethyl acetate (100 mL) and saturatedaqueous sodium bicarbonate (100 mL). The organic layer was separated,dried (MgSO₄) and evaporated. The yellow oil obtained was purified bycolumn chromatography on silica gel eluting with 20-100% ethyl acetatein hexanes, to give the lactol. ¹H NMR (CDCl₃) 7.41-7.30 (4H, m),7.15-7.06 (2H, m), [1H, 5.48-5.46 (m) and 4.60 (d, J=8.8 Hz)], [1H,4.11-4.07 (m) and 3.91-3.98(m)], 3.41-3.40 (2H, m), and 2.95-2.12 (3H,m)

Example 112

The lactol from Example 111 (30 mg, 0.07 mmol) was dissolved indichloromethane (3 mL), methanol (1 mL) and was treated with Amberlyst15 (10 mg) at r.t. over 16 hrs. The mixture was filtered and evaporatedto give a pale oil (30 mg) which was purified by preparative t.l.c togive the ethyl acetal. ¹H NMR (CDCl₃) 7.40-7.26 (4H, m), 7.02-6.88 (2H,m), 6.80-6.73 (1H, m), [1H, 5.01-4.99 (m) and 4.26 (d, J=8.8 Hz)], [2H,4.11-4.07 (m) and 3.87-3.78(m)], 3.49-3.18 (2H, m), 2.90-2.16 (4H,m) and[3H, 1.20 (t, J=6.8 Hz) and 0.80 (t, J=7.2)]

Example 113

Intermediate 1 (2.5 g, 8.3 mmol) was dissolved in dimethylformamide (6mL), and added dropwise to a suspension of 60% sodium hydride in mineraloil (635 mg 16.6 mmol) in dimethylformamide (6 mL). When theeffervescence had ceased the solution was treated with a solution ofN—Boc-bis-(2-chloroethyl)amine (3.75 g, 12 mmol) in dimethylformamide (3mL). The mixture was stirred at r.t. for 36 hrs. Water (800 mL) wasadded and the solution washed with ethyl acetate (2×500 mL). The organicphase washed with brine (500 mL), dried (MgSO₄) and evaporated. Theclear oil obtained was purified by column chromatography on silica geleluting with 5-20% ethyl acetate in hexanes. The oil obtained was thenfurther purified by column chromatography on silica gel eluting withdichloromethane to give the Boc-piperidine. ¹H NMR (CDCl₃) 7.41-7.34(4H, m), 7.13-7.05 (2H, m), 6.91-6.83 (1H, m), 4.25-4.15 (2H, m),2.72-2.56 (4H, m), 2.34-2.23 (2H, m) and 1.43 (9H, s)

Example 114

The Boc piperidine from Example 113 (300 mg, 0.64 mmol) was dissolved indichloromethane (150 mL), and was treated with trifluoroacetic acid (30mL). The mixture was stirred at r.t. for 30 mins and then the solventwas removed in vacuo and saturated aqueous sodium bicarbonate (100 mL)was added. The solution washed with dichloromethane (3×100 mL). Theorganic phase was dried (MgSO₄) and evaporated, to give the piperidineas a white solid. ¹H NMR (CDCl₃) 7.40-7.36 (4H, m), 7.12-7.03 (2H, m),6.91-6.84 (1H, m), 3.18-3.14 (2H, m), 2.75-2.54 (4H, m) and 2.30-2.24(2H, m); MS MH+=371(373).

Example 115

The piperidine from Example 114 (100 mg, 0.3 mmol) was dissolved intoluene (3 mL) and ethyl acetate (2 mL) and was treated with methylbromoacetate (125 μL, 1.5 mmol) and was heated at 90° C. for 1 hr. Thesolvent was evaporated and the clear oil obtained was purified by columnchromatography on silica gel eluting with 5-20% ethyl acetate inhexanes, to give the N-alkylpiperidine. ¹H NMR (CDCl₃) 7.43-7.38 (4H,m), 7.13-7.04 (2H, m), 6.91-6.84 (1H, m), 3.66(3H, s), 3.12 (2H, s),3.02-2.97 (2H, m), 2.90-2.60 (2H, m), 2.51-2.44 (2H, m) and 2.22-2.15(2H, m); MS MH+=443(445).

Example 116

The piperidine from Example 114 (35 mg, 0.09 mmol) was dissolved indichloromethane (2 mL) and was treated with triethylamine (20 μL, 0.14mmol), methyl succinate mono-ester (15 mg, 0.11 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (24 mg, 0.12mmol) and the mixture was stirred at r.t. for 24 hrs. The mixture wasdiluted with water (2 mL) and separated on a Bond Elut™ cartridge beforepurifying by preparative t.l.c to give the amide. ¹H NMR (CDCl₃)7.42-7.35 (4H, m), 7.14-7.07 (2H, m), 6.94-6.88 (1H, m), 4.70-4.64 (1H,m), 4.03-3.97 (1H, m), 3.67 (3H, s), and 3.08-2.25 (10H, m); MSMH+=485(487).

Example 117

The piperidine from Example 114 (56 mg, 0.15 mmol) was dissolved indimethylformamide (2 mL) and was treated with allyl bromide (17 μL, 0.18mmol), and potassium carbonate (63 mg, 0.45 mmol) and the mixture wasstirred at r.t. for 4 hrs. The mixture was diluted with water (2 mL) andthe solution washed with ethyl acetate (3×10 mL). The organic phase wasdried (MgSO₄) and evaporated to give a pale oil which was purified bycolumn chromatography on silica gel eluting with 80% ethyl acetate inhexanes to give the N-allylpiperidine. ¹H NMR (CDCl₃) 7.42-7.37 (4H, m),7.13-7.02 (2H, m), 6.90-6.83 (1H, m), 5.83-5.71 (1H, m), 5.12-5.08 (2H,m), 2.99-2.95 (2H, m), 2.86 (2H, d, J=6.5 Hz), 2.84-2.38 (4H, m), and1.91-1.85 (2H, m); MS MH+=412(414).

Example 118

The azide from Example 38 (130 mg, 0.31 mmol) was dissolved intrimethylsilylacetylene (1.7 mL) and toluene (4 mL) and was heated at90° C. for 7 hrs. The mixture was evaporated to dryness and purified bycolumn chromatography on silica gel eluting with 20% ethyl acetate inhexanes to give the TMS triazole which was dissolved in tetrahydrofuran(16 mL) and was treated with acetic acid (0.3 mL) and TBAF (1M intetrahydrofuran, 2 mL). The mixture was stirred at r.t. for 16 hrs. Thesolvent was removed in vacuo and saturated aqueous sodium bicarbonate(10 mL) was added. The solution washed with ethyl acetate (3×100 mL).The organic phase was dried (MgSO₄) and evaporated, to give a pale oilwhich was purified by column chromatography on silica gel eluting with80% ethyl acetate in hexanes to give the triazole as a white solid. ¹HNMR (CDCl₃) 7.77 (1H, s), 7.69 (1H, s), 7.39-7.32 (4H, m), 7.15-7.06(2H, m), 6.91-6.86 (1H, m), 4.59-4.55 (1H, m), 3.28-3.23 (2H, m),2.68-2.52 (5H, m) and 1.97-1.92 (2H, m); MS MH+=437(439).

Example 119

The cycloheptene from Example 91 (1.43 g, 3.75 mmol) in tetrahydrofuran(20 ml) at 0° C. was treated with borane (18.7 ml, 18.7 mmol, 1Msolution in tetrahydrofuran), and the reaction mixture stirred for 1hour at 0° C. Hydrogen peroxide (27% w/w in water, 30 ml) was mixed withsodium hydroxide solution (4N, 30 ml), then added slowly to thereaction, and stirring continued for a further hour, warming to roomtemperature. The reaction mixture was extracted with ethyl acetate(3×100 ml), and the combined organics were washed with brine (sat., 200ml), dried (MgSO₄) and evaporated in vacuo to give 1.31 g mixture ofisomeric cycloheptanols.

Example 120, 121

The cycloheptanol mixture from Example 119 (48 mg, 0.12 mmol) wasdissolved in dichloromethane (5 mL) and treated with Dess-Martinperiodinate (61 mg, 0.12 mmol), and the mixture stirred at r.t. for 1hr. The mixture was diluted with saturated aqueous sodium bisulphite (5mL) and after 15 mins was treated with saturated aqueous sodiumbicarbonate, (10 mL) then extracted with dichloromethane (3×50 mL). Theorganic phase was dried (MgSO₄) and evaporated, to give a pale oil whichwas purified by preparative t.l.c to give the cycloheptan-3-one (Ex.107): ¹H NMR (CDCl₃) 7.42-7.33 (4H, m), 7.11-7.01 (2H, m), 6.94-6.87(1H, m), 3.66 (1H, dt, J=16.4 and 2.8 Hz), 2.50 (1H, dd, J=16.4 and 5.6Hz), 2.32-2.16 (2H, m), 1.86-1.78 (2H, m), and 1.67-1.52 (2H, m);

and the cycloheptan-4-one (Ex. 108): ¹H NMR (CDCl₃) 7.41-7.34 (4H, m),7.13-7.07 (1H, m), 7.01-6.97 (1H, m), 6.95-6.88 (1H, m), 3.06-3.00 (2H,m), 2.65-2.44 (4H, m), 2.41-2.33 (1H, m), 2.09-2.01 (1H, m), and1.58-1.50 (2H, m).

Example 122

The ketone from Example 121 (40 mg, 0.1 mmol) was dissolved indichloroethane (3 mL) and was treated with morpholine (16 mg, 0.26 mmol)and sodium triacetoxyborohydride (42 mg, 0.26 mmol) and the mixturestirred at r.t. for 16 hrs. The mixture was diluted with saturatedaqueous sodium bicarbonate (1 mL) and was separated on a Bond Elut™cartridge before passing through a SCX Bond Elut™ cartridge. The basicfraction was purified by preparative t.l.c to give the amine. ¹H NMR(CDCl₃) 7.38-7.31 (4H, m), 7.07-6.95 (2H, m), 6.91-6.84 (1H,m),3.73-3.61 (5H,m) and 2.72-1.21 (11H, m); MS MH+ 469(471).

Example 123

The cycloheptan-4-one from Example 121 (200 mg, 0.5 mmol) was dissolvedin acetic acid (18 mL) and water (2 mL) and was treated with cericammonium nitrate (138 mg, 0.25 mmol) and bromine (40 mg, 0.25 mmol) andthe mixture was heated at 50° C. for 16 hrs. The mixture was dilutedwith water (100 mL) and was extracted with ether (3×75 mL), the organiclayer was dried (MgSO₄) and evaporated, give a mixture of bromoketones,which were dissolved in glyme (7.5 mL) and treated with sodium methoxide(43 mg, 3 eq). The mixture was stirred at room temperature for 2 hrsbefore quenching with acetic acid (0.5 mL), the mixture was diluted withwater (30 mL) and extracted with ethyl acetate (3×25 mL). The organiclayer was dried (MgSO₄) and evaporated, to give a mixture of esters. The4-isomer was isolated by preparative t.l.c. ¹H NMR (CDCl₃) 7.38-7.32(4H, m), 7.09-7.02 (2H, m), 6.89-6.83 (1H,m), 3.74 (3H, s), 2.62-2.53(3H,m), 2.33-2.24 (4H, m) and 1.51-1.41 (2H, m); MS MH+ 469(471).

Example 124

Step (1)

The ketone from Example 2 (5 g, 13 mmol) was dissolved intetrahydrofuran (100 ml) and was added at −78° C. to a solution of LDA(28.6 mmol) in tetrahydrofuran (200 ml). The mixture was warmed to −30°C. over 1 hr and then recooled to −78° C. before treating with N-phenyltriflamide (4.65 g, 13 mmol) and the mixture was allowed to warm to rtover 16 hr. The mixture was diluted with water (2 ml) and the solutionwashed with ethyl acetate (2×500 ml). The organic phase washed withbrine (500 ml), dried (MgSO₄) and evaporated. The clear oil obtained waspurified by column chromatography on silica gel eluting with 5-20% ethylacetate in hexanes. The oil obtained was then further purified by columnchromatography on silica gel eluting with 5-10% ethyl acetate in hexaneto give4-(2,5-difluorophenyl)-4-(4-chlorophenylsulphonyl)-1-trifluoromethylsulphonylcyclohex-1-ene.

¹H NMR (CDCl₃) 7.42-7.36 (4H, m), 7.10-7.04 (2H, m), 6.91-6.83 (1H, m),5.77-5.76 (1H, m), 3.14-3.12 (2H, m), 3.01-2.95 (1H, m), 2.57-2.44 (2H,m) and 2.24-2.14 (1H, m).

Step (2)

The triflate from step (1) (260 mg, 0.6 mmol), cesium carbonate (357 mg,1.2 mmol) and phenyl boronic acid (94 mg, 0.76 mmol) were dissolved indimethoxyethane/water [9:1] (20 ml). The flask was degassed and thentetrakistriphenylphosphine palladium (25 mg) was added, the mixturewarmed to reflux over 4 hr and then cooled to rt. The solution wasfiltered through Celite™ and was diluted with water (20 ml) The solutionwashed with ethyl acetate (2×100 ml). The organic phase washed withbrine (100 ml), dried (MgSO₄) and evaporated. The clear oil obtained waspurified by column chromatography on silica gel eluting with 5% ethylacetate in hexanes, to give the desired product. ¹H NMR (CDCl₃)7.44-7.38 (4H, m), 7.25-7.17 (5H, m), 7.13-7.07 (1H, m), 7.01-6.96 (2H,m), 6.86-6.79 (1H, m), 6.09-6.07 (1H, m), 3.16-3.14 (2H, m), 3.07-3.02(1H, m), 2.73-2.67 (1H,m), 2.49-2.45 (1H, m) and 2.28-2.25 (1H, m).

Example 125

The alkene from Example 124 (60 mg, 0.13 mmol) was dissolved in ethanol(5 ml). The flask was degassed and then 5% palladium on carbon (5 mg)was added the mixture was stirred under an atmosphere of hydrogen for 45mins. The solution was filtered through Celite™ and evaporated. Theclear oil obtained was purified by preparative tlc eluting with 5% ethylacetate in hexanes. The oil obtained was then further purified by columnchromatography on silica gel eluting with 5% ethyl acetate in hexane togive the cis isomer; ¹H NMR (CDCl₃) 7.38 (4H, s), 7.25-7.00 (7H, m),6.91-6.84 (1H, m), 3.08-3.06 (1H, m), 2.75-2.69 (2H, m), 2.38-2.31 (2H,m), 2.04-2.00 (2H,m) and 1.44-1.38 (2H, m); and the trans isomer ¹H NMR(CDCl₃) 7.42-7.37 (8H, m), 7.34-7.00 (3H, m), 6.91-6.83 (1H, m),2.87-2.75 (3H, m), 2.49-2.40 (1H, m), 2.37-2.26 (2H, m) and 1.90-1.80(1H, m).

Example 126

The trans mesylate from Example 37 (103 mg, 0.22 mmol) was dissolved intoluene (20 ml) and added to a pre-azeotroped sample oftetrabutylammonium cyanide (354 mg, 1.32 mmol), and the mixture waswarmed to 70° C. over 18 hr and then cooled to rt. The solution wasdiluted with water (10 ml) and washed with ethyl acetate (2×50 ml). Theorganic phase washed with brine (10 ml), dried (MgSO₄) and evaporated.The clear oil obtained was purified by column chromatography on silicagel eluting with 10-20% ethyl acetate in hexanes, to give the cyanide.¹H NMR (CDCl₃) 7.42-7.36 (4H, s), 7.10-7.05 (2H, m), 6.89-6.84 (1H, m),2.88-2.86 (1H, m), 2.76-2.72 (2H, m), 2.52-2.45 (1H,m), 2.12-2.07 (1H,m) and 1.56-1.49 (1H, m).

Example 127

The cyanide from Example 126 (143 mg, 0.36 mmol) was dissolved/suspendedin a mixture of glacial acetic acid (10 ml) and conc. HCl (6 ml) andheated at 110° C. for 15 hours. The mixture was cooled, diluted withethyl acetate and washed with water (×3), dried (MgSO₄) and evaporatedto dryness. This crude residue (153 mg) was purified by preparative tlc(5% methanol in dichloromethane/1% acetic acid). ¹H NMR (CDCl₃)7.38-7.35 (4H, s), 7.08-7.06 (2H, m), 6.90-6.84 (1H, m), 2.65-2.58 (2H,m), 2.38-2.33 (3H, m), and 1.75-1.49 (4H, m).

Example 128

The cyanide from Example 126 (50 mg, 0.12 mmol) was dissolved in amixture of tetrahydrofuran (4.5 ml) and water (0.5 ml) and stirred at20° C. The mixture was treated with hydrogen peroxide (20 ml, 0.6 mmol)and then with lithium hydroxide (6 mg, 0.25 mmol) for 2 hours. Hydrogenperoxide (20 ml, 0.6 mmol) and then with lithium hydroxide (6 mg, 0.25mmol) were added and the mixture was stirred at rt. for 72 hrs. Themixture was cooled, diluted with ethyl acetate and washed with water(×2) and sat. sodium bisulphite, dried (MgSO₄) and evaporated todryness. This crude residue (51 mg) was purified by preparative tlc (20%ethyl acetate in hexanes) ¹H NMR (CDCl₃) 7.37 (4H, s), 7.10-7.02 (2H,m), 6.90-6.84 (1H, m), 5.57 (2H, brs), 2.54-2.48 (3H, m), 2.43-2.39 (1H,m), 2.19-2.15 (2H, m) and 1.62-1.50 (3H, m).

Example 129

Step (1)

1-Trifluoromethylsulphonylcyclohex-1-ene (3 g, 13 mmol), cesiumcarbonate (8.4 g, 26 mmol) and 2,5-difluorophenyl boronic acid (2.88 g,18 mmol) were dissolved in dimethoxyethane/water [9:1] (200 ml). Theflask was degassed and then tetrakistriphenylphosphine palladium (125mg) was added, the mixture warmed to 80° C. over 4 hr and then cooled tor.t. The solution was filtered through Celite™, diluted with water (20ml) and the solution washed with ethyl acetate (2×100 ml). The organicphase washed with brine (100 ml), dried (MgSO₄) and evaporated. Theclear oil obtained was purified by column chromatography on silica geleluting with hexanes, to give 1-(2,5-difluorophenyl)cyclohex-1-ene. ¹HNMR (CDCl₃) 6.97-6.73 (3H, m), 5.97-5.96 (1H, m), 2.35-2.31 (2H, m),2.23-2.14 (2H, m) and 1.79-1.68 (1H, m).

Step (2)

The styrene from Step (1) (100 mg, 0.5 mmol) and 4-bromothiophenol (96mg 0.5 mmol) were dissolved in dichloromethane (5 ml) and then 70%aqueous perchloric acid (15 ml) was added. The mixture was stirred atrt. over 24 hr and then treated with m-chloroperoxybenzoic acid indichloromethane (10 ml) with stirring at rt. for a further 6 hrs. Themixture was diluted with 2N sodium hydroxide (2 ml) and separated on aVarian Bond Elut™ cartridge. The organic phase was dried (MgSO₄) andevaporated. The clear oil obtained was purified by column chromatographyon silica gel eluting with 2-5% ethyl acetate in hexanes, to give thesulphone. ¹H NMR (CDCl₃) 7.53 (2H, d, J=8.6 Hz), 7.27 (2H, d, J=8.6 Hz),7.08-7.03 (2H, m), 6.84-6.80 (1H, m), 2.82-2.63 (2H, m), 2.12-2.04 (2H,m), 1.82-1.78 (2H, m) 1.64-1.54 (1H, m) and 1.40-1.18 (3H, m).

Following the procedure of Example 129, using the appropriate thiophenolin Step (2), the compounds of Examples 130-132 were obtained:

Example 130

¹H NMR (CDCl₃) 7.30 (2H, d, J=8.6 Hz), 7.18 (2H, d, J=8.6 Hz), 7.03-6.97(2H, m), 6.85-6.79 (1H, m), 2.85-2.65 (2H, m), 2.41 (3H, s), 2.10-2.03(2H, m), 1.81-1.75 (2H, m) 1.61-1.57 (1H, m) and 1.35-1.13 (3H, m).

Example 131

¹H NMR (CDCl₃) 7.44-7.40 (1H, m), 7.10-7.00 (4H, m), 6.86-6.80 (1H, m),2.82-2.61 (2H, m), 2.12-2.07 (2H, m), 1.82-1.78 (2H, m) 1.62-1.54 (1H,m) and 1.45-1.15 (3H, m).

Example 132

¹H NMR (CDCl₃) 7.58-7.54 (1H, m), 7.34-7.33 (3H,m), 7.10-7.03 (2H, m),6.98-6.81 (1H, m), 2.82-2.61 (2H, m), 2.18-2.07 (2H, m), 1.85-1.79 (2H,m) 1.63-1.58 (1H, m) and 1.40-1.17 (3H, m).

Example 133

To the cis alcohol from Example 22 (1.8 g, 4.7 mmol) in dry THF (10 ml)under nitrogen were added sodium hydride (60% dispersion, 740 mg, 18.6mmol) and potassium ^(t)butoxide (1M in THF solution, 0.47 ml, 0.47mmol). Allyl bromide (1.2 ml, 14.1 mmol) was added and the reactionheated at 60° C. for 18 h., diluted with water and extracted with ethylacetate (×3). Organic extracts were washed with brine, dried (MgSO₄),filtered and evaporated. Crude product purified by flash columnchromatography (2:1 ^(i)hexane/ethyl acetate) to give a light yellowsemi-solid (1.0 g). ¹H NMR (CDCl₃) 1.24-1.32 (2H, m), 1.97 (1H, s), 2.03(1H, d, J=9.5 Hz), 2.51 (4H, d, J=11.2 Hz), 3.47 (1H, t, J=2.8 Hz), 3.94(1H, t, J=1.6 Hz), 3.96 (1H, t, J=1.4 Hz), 5.17-5.27 (2H, m), 5.86-5.96(1H, m), 6.83-6.90 (1H, m), 7.02-7.14 (2H, m), 7.38 (4H, s).

Example 134

The allyl ether (200 mg, 0.47 mmol) from example 133 was dissolved incarbon tetrachloride (10 ml), water (1 ml), and acetonitrile (1 ml). Thesolution was stirred vigorously and sodium metaperiodate (402 mg, 1.88mmol) and ruthenium trichloride hydrate (2 mg) were added. After 2 h thereaction was diluted with DCM and filtered through Celite™. The filtratewas concentrated and partitioned between ethyl acetate and water.Organic extracts were washed with brine, dried (MgSO₄), filtered andevaporated. Crude product purified by flash column chromatography (ethylacetate) to give a white solid (80 mg). ¹H NMR (CDCl₃) 2.04 (5H, br),2.30-2.59 (4H, m), 3.63-3.67 (1H, br), 4.05 (2H, br), 6.79 (1H, br),6.99 (2H, br), 7.29 (4H, br).

Example 135

The allyl ether (120 mg, 0.28 mmol) from Example 133 was dissolved indry THF (5 ml). To the solution under nitrogen and cooled to 0° C. wasadded a borane-THF solution (1M, 0.56 ml, 0.56 mmol), via a syringe,over 5 minutes. The reaction was stirred at this temperature for 4 h andthen water (0.5 ml) was added followed by aq. sodium hydroxide (2M, 0.5ml) and 30% hydrogen peroxide (0.4 ml). Reaction was stirred for 15 h atroom temperature, concentrated, and partitioned between ethyl acetateand water. Organic extracts were washed with brine, dried (MgSO₄),filtered and evaporated. Crude product purified by flash columnchromatography (1:1 ^(i)hexane/ethyl acetate) to give a colourless oil(80 mg). ¹H NMR (CDCl₃) 1.81-1.88 (2H, m), 1.98 (1H, s), 2.03 (2H, d,J=8.4 Hz), 2.07 (1H, s), 2.46 (5H, dd, J=0.7, 0.7 Hz), 3.44 (1H, t,J=2.8 Hz), 3.57 (2H, t, J=5.8 Hz), 3.78 (2H, s), 6.83-6.90 (1H, m),7.02-7.13 (2H, m), 7.38 (4H, s).

Example 136

Step (1)

The acid from Example 134 (560 mg, 1.2 mmol) was dissolved in ethylacetate (100 ml) under nitrogen and pentafluorphenol (330 mg, 1.8 mmol)was added. The solution was cooled to 0° C., dicyclohexylcarbodiimide(370 mg, 1.8 mmol) added, and the reaction was allowed to warm to roomtemperature and stirred for 1 h. The reaction mixture was filteredthrough a pad of Celite™, the filtrate evaporated and purified by flashchromatography (2:1 ^(i)hexane/ethyl acetate) to give thepentafluorophenol ester as a white solid (760 mg).

Step (2)

To this ester (115 mg, 0.18 mmol) was added a 2 M solution of ammonia inmethanol (3 ml), and the mixture heated at 50° C. in a sealed tube for 3h. The reaction mixture was concentrated and purified by flashchromatography (1:1 ^(i)hexane/ethyl acetate to 9:1 ethylacetate/methanol) to give a white solid (54 mg). ¹H NMR (CDCl3)1.32-1.40 (2H, m), 2.04 (2H, br), 2.51-2.54 (4H, m), 3.54 (1H, t, J=2.8Hz), 3.95 (2H, s), 5.45-5.54 (1H, br), 6.50-6.59 (1H, br), 6.83-6.90(1H, m), 7.03-7.14 (2H, m), 7.36-7.40 (4H, m)

Example 137

To the pentafluorophenol ester prepared in Example 136 (125 mg, 0.2mmol) dissolved in DCM (3 ml) and under nitrogen was added N-methylpiperazine (70 μl, 0.8 mmol). After 1 h the reaction was concentrated,diluted with ethyl acetate, washed with aq. sodium carbonate, water,brine, dried (MgSO₄), filtered and evaporated. Purified by flash columnchromatography (1:1 ^(i)hexane/ethyl acetate to 9:1 ethylacetate/methanol+2% triethylamine) to give a colourless glassy solid (50mg). ¹H NMR (CDCl₃) 1.34 (2H, m), 2.02 (4H, m), 2.34 (2H, m), 2.40-2.55(8H, m), 3.55 (1H, t, J=2.8 Hz), 3.63 (2H, t, J=4.9 Hz), 4.14 (3H, s),6.82-6.89 (1H, m), 7.02-7.12 (2H, m), 7.36 (4H, d, J=4.6 Hz).

Example 138

Prepared as in Example 137, using thiomorpholine sulfone hydrochloride(120 mg, 0.7 mmol) and triethylamine (0.1 ml) in place ofN-methylpiperazine, to give a white solid (50 mg). ¹H NMR (CDCl₃)1.31-1.39 (2H, m), 2.00 (1H, s), 2.05 (1H, s), 2.38-2.45 (3H, m),2.51-2.65 (1H, m), 3.09 (2H, d, J=1.1 Hz), 3.22 (2H, s), 3.58 (1H, t,J=2.5 Hz), 4.13 (4H, d, J=3.2 Hz), 4.18 (2H, s), 6.82-6.89 (1H, m),7.03-7.12 (2H, m), 7.34 (3H, d, J=14.7 Hz), 7.39 (1H, s).

Example 139

To the alcohol prepared in Example 22b (150 mg, 0.39 mmol) in dry THF (5ml) cooled to 0° C. and under nitrogen was added chlorosulfonylisocyanate (50 μl, 0.54 mmol). The reaction was stirred for 1 h and thensodium metabisulfite (220 mg, 1.17 mmol) in water (2 ml) was addeddropwise over 5 min. Reaction was allowed to warm to room temperatureand stirred for 16 h., diluted with water and extracted with ethylacetate (×3). Organic extracts were washed with brine, dried (MgSO₄),filtered and evaporated. The carbamate was isolated by trituration withether to give a white solid (40 mg). MS (EI+) 427 (M−2H)

Example 140

To 3-(ethoxycarbonyl)propyltriphenylphosphonium bromide (238 mg, 0.52mmol) in dry toluene (5 ml) and under nitrogen was added dropwisepotassium hexamethyldisilazide (0.5 M in toluene, 1.2 ml). The ketonefrom Example 2 (100 mg, 0.26 mmol) in dry toluene (3 ml) was added, thereaction stirred at 100° C. for 5 h., cooled, diluted with water and theorganic layer removed. The aqueous layer was extracted with ethylacetate (×3). Organic extracts were washed with brine, dried (MgSO₄),filtered and evaporated. Crude product purified by flash columnchromatography (2:1 ^(i)hexane/ethyl acetate) to give a white foam (70mg). ¹H NMR (CDCl₃) 1.24 (3H, t, J=7.2 Hz), 1.64-1.71 (2H, m), 1.93-2.38(5H, m) 2.70-2.80 (4H, m), 4.13 (2H, q, J=7.1 Hz), 5.12 (1H, s),6.83-6.91 (1H, m), 7.02-7.16 (3H, m), 7.37 (4H, s).

Example 141

The trans-3-alcohol from Example 99 (40.0 mg, 0.104 mmol) inN,N-dimethylformamide (2 ml) was treated with allyl bromide (26.4 μl,0.312 mmol), followed by sodium hydride (6.2 mg, 60% w/w in mineral oil,0.156 mmol) and stirred at room temperature. After 2 hours, furtherportions of allyl bromide (26.4 μl, 0.312 mmol) and sodium hydride (6.2mg, 60% w/w in mineral oil, 0.156 mmol) were added and stirring at roomtemperature continued. After 4 hours, reaction was quenched with water(60 ml), extracted with ethyl acetate (3×40 ml). Combined organics werewashed with brine (sat., 150 ml), dried (MgSO₄) and concentrated invacuo to give crude product (45 mg). This material was purified bypreparative t.l.c., eluting with 15% ethyl acetate in hexanes to giveproduct (25 mg, 56%). ¹H NMR (400 MHz, CDCl₃) 1.53-1.81 (3H, m),2.29-2.35 (1H, m), 2.45 (2H, d, J=13.8 Hz) 2.95-3.00 (1H, br), 3.80-3.82(2H, m), 3.91-3.92 (2H, m), 4.89-4.98 (2H, m), 5.58-5.68 (1H, m),6.74-6.80 (1H, m), 6.93-7.02 (2H, m), 7.29-7.38 (4H, m).

Example 142

The cis-3-alcohol from Example 93 (87.0 mg, 0.226 mmol) inN,N-dimethylformamide (3 ml) was dripped into a suspension of sodiumhydride (27.1 mg, 60% w/w in mineral oil, 0.678 mmol) inN,N-dimethylformamide (1 ml). Ethyl bromoacetate (75.2 μl, 0.678 mmol)was added and reaction stirred at room temperature. After 2 hours afurther portion of ethyl bromoacetate (75.2 μl, 0.678 mmol) was added,the mixture stirred at room temperature for a further 4 hours, thenheated to 90° C. for 3.5 hours. Reaction was then cooled, furtherportions of sodium hydride (27.1 mg, 60% w/w in mineral oil, 0.678 mmol)and ethyl bromoacetate (75.2 μl, 0.678 mmol) added, and heated again to90° C. After 4 hours at this temperature, reaction was cooled, dilutedwith water (150 ml) and extracted with ethyl acetate (3×100 ml).Combined organics were washed with brine (sat., 250 ml), dried (MgSO₄)and evaporated in vacuo to give crude (263 mg). Crude material waschromatographed on silica, eluting with 15% ethyl acetate in hexanes togive impure product (32 mg) which was purified further by preparativet.l.c., eluting with 15% ethyl acetate in hexanes, followed by a secondpreparative t.l.c., eluting with 100% dichloromethane to give product (7mg, 7%). ¹H NMR (400 MHz, CDCl₃), 1.22-1.38 (3H, m), 1.89-1.94 (1H, m),2.00-2.05 (3H, br), 2.60-3.15 (2H, m), 3.19-3.26 (1H, m), 4.07 (2H, s),4.16-4.26 (4H, m), 6.84-6.95 (1H, m), 7.02-7.11 (2H, m), 7.39 (4H, s).

Example 143

The cis-allyl ether from Example 101 (50.0 mg, 0.108 mmol) in carbontetrachloride (0.2 ml), water (0.3 ml) and acetonitrile (0.2 ml) wastreated with sodium (meta)periodate (95.0 mg, 0.444 mmol) followed byruthenium(III) chloride hydrate (2.2 mol %, 0.5 mg, 2.38 nmol). Afterstirring at room temperature for 2 hours, dichloromethane (2 ml) wasadded and the phases separated. Aqueous phase was extracted withdichloromethane (3×5 ml). Combined organics were dried (MgSO₄) andevaporated in vacuo to give a brown residue (44 mg). This residue wasdiluted in diethyl ether (10 ml) and filtered through a pad of Celite™,then concentrated in vacuo to give crude (34 mg). This material waspurified by preparative t.l.c., eluting with 5% methanol, 1% acetic acidin dichloromethane to give product (27 mg, 56%). ¹H NMR (400 MHz,(CD₃)₂SO), 0.99-1.23 (2H, br), 1.70-1.86 (2H, br), 1.87-1.99 (1H, br),2.55-3.05 (2H, br), 3.09-3.22 (1H, br), 3.24-3.40 (2H, br), 3.85-4.05(1H, br), 7.10-7.20 (2H, br), 7.25-7.35 (1H, br), 7.41 (2H, d, J=7.9Hz), 7.64 (2H, d, J=8.0 Hz), 12.10-12.80 (1H, br).

Example 144

The cis-allyl ether from Example 101 (100 mg, 0.235 mmol) indichloromethane/methanol (1:1, 10 ml) was cooled to −78° C. The flaskwas purged with oxygen, then with ozone until saturated, then withoxygen again and finally nitrogen. The mixture was warmed to roomtemperature and dimethyl sulphide (159 μl, 2.35 mmol) added. Thereaction was then allowed to warm to room temperature and stirringcontinued for a further 16 hours. Solvent was removed in vacuo and theresidue partitioned between water (10 ml) and ethyl acetate (10 ml). Theaqueous phase was separated and extracted with ethyl acetate (2×10 ml).Combined organics were washed with brine (sat., 40 ml), dried (MgSO₄)and evaporated in vacuo to give the cyclohexyloxyacetaldehyde derivative(102 mg, >99%). ¹H NMR (400 MHz, CDCl₃), 1.16-1.25 (1H, br), 1.32-1.40(1H, br), 1.90-1.96 (2H, m), 2.02-2.10 (2H, br), 2.30-3.00 (2H, br),3.18-3.23 (1H, m), 4.09 (2H, s), 6.84-6.91 (1H, m), 7.03-7.09 (2H, m),7.36-7.41 (4H, m), 9.68 (1H, s).

The aldehyde (102 mg, 0.238 mmol) in dichloroethane (10 ml) was thentreated with morpholine (22.9 μl, 0.262 mmol). After stirring at roomtemperature for 2 hours, the mixture was treated with sodiumtriacetoxyborohydride (202 mg, 0.852 mmol) and glacial acetic acid (1ml). After a further 1.5 hours at room temperature, solvent was removedin vacuo and the residue partitioned between dichloromethane (5 ml) andsodium hydrogen carbonate (sat. aq., 5 ml). The organic phase wasseparated on a Varian Bond Elut™ cartridge and purified on a SCX VarianBond Elut™ cartridge. Solvent was removed in vacuo to give product (80mg, 67%). ¹H NMR (400 MHz, CDCl₃), 1.15-1.32 (2H, m), 1.87-1.99 (4H, m),2.47-2.49 (4H, m), 2.54 (2H, t, J=6.0 Hz), 2.60-3.00 (2H, br), 3.08-3.16(1H, br), 3.56-3.63 (2H, m), 3.70 (4H, t, J=4.6 Hz), 6.84-6.90 (1H, m),7.03-7.08 (2H, m), 7.36-7.41 (4H, m); ms. (ES⁺), 500 (M⁺+1), 324(M⁺175), 193 (M⁺306).

Example 145

The cyclohexene from Example 34 (493 mg, 1.34 mmol) andN-methylmorpholine-N-oxide (204 mg, 1.74 mmol) in tetrahydrofuran/water(3:1, 8 ml) were stirred during the addition of osmium tetroxide (107μl, 2.5 wt. % in ^(t)BuOH, 0.342 mmol). Mixture was stirred for 24 hoursat room temperature, then another portion of osmium tetroxide (107 μl,2.5 wt. % in ^(t)BuOH, 0.342 mmol) was added and stirring continued fora further 5 hours. The reaction mixture was diluted with sodium hydrogensulfite (sat., aq., 15 ml) then extracted with ethyl acetate (3×15 ml).Combined organics were washed with brine (sat., 50 ml), dried (MgSO₄)and evaporated in vacuo to give product (88:12 cis:trans) (509 mg, 94%).¹H NMR (400 MHz, CD₃OD), 1.31-1.39 (1H, m), 1.92 (1H, qd, J=14.6 Hz andJ=3.1 Hz), 2.40-2.62 (4H, br), 3.33-3.38 (1H, m), 3.78 (1H, d, J=2.7Hz), 6.97-7.10 (1H, m), 7.16-7.21 (2H, m), 7.43 (2H, d, J=8.5 Hz), 7.52(2H, d, J=8.6 Hz).

Example 146

The mixture of diols from Example 145 (100 mg, 0.249 mmol) in acetone (3ml) was treated with para-toluenesulphonic acid monohydrate (30.0 mg,0.158 mmol) and the mixture stirred at room temperature. After 4 hours,a further portion of para-toluenesulphonic acid monohydrate (50.0 mg,0.263 mmol) was added and the reaction mixture heated to 60° C. for 1hour, then stirring continued at room temperature for a further 24hours. Solvent was then removed in vacuo and the residue partitionedbetween ethyl acetate (10 ml) and sodium hydrogen carbonate (sat. aq.,10 ml). The aqueous phase was separated and extracted with ethyl acetate(2×10 ml). Combined organics were then washed with brine (sat., 50 ml),dried (MgSO₄) and evaporated in vacuo to give crude (77 mg). Thismaterial was chromatographed on silica, eluting with 20% ethyl acetatein hexanes, followed by further purification by preparative t.l.c.,eluting with 30% ethyl acetate in hexanes to give product (7.7 mg, 7%).¹H NMR (400 MHz, CDCl₃), 1.31 (3H, s), 1.54 (3H, s), 1.59-1.66 (1H, m),2.14-2.20 (1H, m), 2.26-2.32 (1H, m), 2.35-2.42 (1H, m), 2.54-2.58 (1H,br), 2.81-2.86 (1H, br), 3.95-4.03 (2H, m), 6.83-6.89 (1H, m), 7.03-7.11(2H, m), 7.36-7.41 (4H, m).

Example 147

The mixture of diols from Example 145 (100 mg, 0.249 mmol) in toluene (3ml) was treated with N-Fmoc-4-piperidone (240 mg, 0.747 mmol) andpara-toluenesulphonic acid monohydrate (10 mg). This mixture was heatedto reflux under Dean-Stark conditions. After 3 hours, solvent wasremoved in vacuo to give crude (420 mg). This material waschromatographed on silica, eluting with 25% ethyl acetate in hexanes togive protected acetal (148 mg, 84%).

This material was treated with 20% diethylamine in dichloromethane (5ml). After stirring at room temperature for 16 hours, solvent wasremoved in vacuo to give crude (343 mg). This material waschromatographed on silica, eluting with dichloromethane/methanol/ammonia(90:8:1) to give material which was purified further by preparativet.l.c., eluting with dichloromethane/methanol/ammonia (90:8:1) givingproduct (40 mg, 39%). ¹H NMR (360 MHz, CDCl₃), 1.58-1.70 (3H, br),1.83-1.88 (2H, m), 2.17 (1H, dt, J=10.2 Hz and J=2.0 Hz), 2.31-2.58 (3H,br), 2.84-3.02 (3H, m), 3.00 (2H, t, J=5.7 Hz), 3.97-4.03 (2H, m),6.81-6.88 (1H, m), 7.02-7.11 (2H, m), 7.34-7.40 (4H, m).

Example 148

Prepared by the methods of Examples 1 and 2. The sulphone used for theprocess of Example 1 was obtained in the same manner as Intermediate 1,using 2-fluoro-5-iodobenzyl bromide in place of 2,5-difluorobenzylbromide. ¹H NMR (360 MHz, CDCl₃) 2.18 (2H, dt, J=5.5, 16.4 Hz),2.52-2.59 (4H, m), 2.97-3.06 (2H, m), 6.76 (1H, dd, J=8.6, 12.7 Hz),7.36-7.44 (4H, m), 7.56 (1H, dd, J=2.1, 7.5 Hz), 7.69-7.73 (1H, m).

Example 149

Prepared by the methods of Examples 1 and 2. The sulphone used for theprocess of Example 1 was obtained in the same manner as Intermediate 1,using 2-fluoro-5-bromobenzyl bromide in place of 2,5-difluorobenzylbromide. ¹H NMR (360 MHz, CDCl₃) 2.19 (2H, dt, J=5.2, 16.3 Hz),2.53-2.59 (4H, m), 2.98-3.06 (2H, m), 6.88 (1H, dd, J=8.7, 12.5 Hz),7.37-7.55 (6H, m).

Example 150

A solution of Intermediate 1 (10 g) in THF (100 ml) was cooled to −30°C. and treated slowly with n-BuLi (1.6 M in hexane, 22 ml). The reactionwas stirred for 30 mins, then treated with epichlorohydrin, warmed toroom temperature and refluxed for 30 min. The reaction mixture wascooled, evaporated and partitioned between water/EtOAc. The aqueouslayer was dried, filtered and evaporated. Purification by columnchromatography gave the alcohol (5 g, 42%) as a white solid. ¹H NMR (360MHz, CDCl₃) 7.41-7.35 (4H, m), 7.04-6.97 (1H, m), 6.85-6.76 (2H, m),4.34-4.24 (1H, m), 3.59 (1H, d, J=10.7 Hz), 3.13-3.11 (4H, m).

Example 151

A solution of the alcohol from Example 150 (3 g) in DMF (20 ml) wastreated with sodium hydride (1.5 equiv.) and allyl bromide (2 equiv.)and stirred at room temperature for 1 h. The reaction mixture wasdiluted with 1N HCl and ethyl acetate. The organic phase washed, dried,filtered and evaporated. Purification by column chromatography gave theallyl ether (3 g, 89%) as a white solid. ¹H NMR (400 MHz, CDCl₃)7.39-7.34 (4H, m), 7.04-6.99 (1H, m), 6.95-6.91 (1H, m), 6.85-6.79 (1H,m), 5.94-5.85 (1H, m), 5.29-5.17 (2H, m), 3.94-3.84 (3H, m), 3.23-3.18(2H, m), 3.00-2.95 (2H, m).

Example 152

A solution of the allyl ether from Example 151 (2 g) was dissolved in^(t)BuOH (20 ml), THF (20 ml) and water (1 ml) and treated withN-methylmorpholine-N-oxide (3 equiv.) and OsO₄ (2.5 wt % solution in^(t)BuOH, 2 ml) and stirred at room temperature for 1 h. The reactionmixture was treated with sodium sulfite (3 equiv.), stirred for 10 min,then diluted with water/EtOAc. The organic phase was dried, filtered andevaporated. Purification by column chromatography gave the diol (2.1 g,97%) as a white solid. ¹H NMR (360 MHz, CDCl₃) 7.37 (4H, s), 7.05-6.98(1H, m), 6.93-6.88 (1H, m), 6.83-6.77 (1H, m), 3.99-3.87 (2H, m),3.79-3.64 (2H, m), 3.53-3.44 (2H, m), 3.25-3.19 (2H, m), 3.03-2.97 (2H,m), 2.83 (1H, d, J=4.8 Hz), 2.09 (1H, t, J=6.1 Hz).

Example 153

A solution of the diol from Example 152 (2 g) was dissolved in methanol(20 ml) and water (20 ml) and treated with sodium periodate (3 equiv.)and stirred at room temperature for 10 min. The reaction mixture wasdiluted with ether and water. The organic layer washed, dried, filteredand evaporated in vacuo to give the corresponding aldehyde. Thiscompound was dissolved in ^(t)BuOH (20 ml) and water (6 ml) and treatedwith NaClO₂ (3 equiv.) and NaH₂PO₄.2H₂O (1.05 equiv.) and stirred atroom temperature for 1 h. The reaction mixture was quenched with 1N HCl,ethyl acetate and water. The organic phase washed, dried, filtered andevaporated. Purification by column chromatography gave the acid as awhite solid (1.2 g, 81%). ¹H NMR (360 MHz, DMSO) 12.8 (1H, brs),7.62-7.60 (2H, m), 7.43-7.39 (2H, m),7.32-7.03 (3H, m), 3.99 (2H, s),3.92 (1H, qt, J=7.4 Hz), 3.07-2.96 (4H, m).

Example 154

A solution of the acid from Example 153 (0.8 g) was dissolved in ethylacetate (10 ml) and treated with C₆FsOH (1.5 equiv.) and DCC (1.5equiv.) and stirred at room temperature for 15 min. The reaction mixturewas filtered and evaporated in vacuo and used without furtherpurification.

A solution of the resulting active ester (ca. 0.64 mmol) in DCM (3.33ml) was treated with ammonia gas and stirred at room temperature for 10min. The reaction mixture was evaporated in vacuo and purified by columnchromatography to give the amide (120 mg, 45%) as a white solid. ¹H NMR(400 MHz, DMSO) 7.61 (2H, d, J=8.7 Hz), 7.41 (2H, d, J=8.7 Hz),7.30-6.99 (5H, m), 3.95-3.88 (1H, m), 3.76 (2H, s), 3.09-2.93 (4H, m).

Example 155

Prepared in 47% yield by a procedure analogous to Example 154. ¹H NMR(400 MHz, DMSO) 7.70 (1H, brd), 7.63-7.61 (2H, m), 7.41-7.40 (2H, m),7.32-7.27 (1H, m), 7.17-7.09 (1H, m), 7.07-7.02 (1H, m), 3.95-3.85 (1H,m), 3.80 (2H, s), 3.04-3.01 (4H, m), 2.61 (3H, d, J=4.8 Hz).

Example 156

Prepared in 35% yield in a procedure analogous to Example 154. ¹H NMR(400 MHz, DMSO) 7.63-7.61 (2H, m), 7.42-7.40 (2H, m), 7.33-7.25 (1H, m),7.17-7.01 (2H, m), 4.10 (2H, s), 3.95-3.85 (1H, m), 3.08-2.94 (4H, m),2.88 (3H, s), 2.79 (3H, s).

Example 157

A solution of the allyl ether from Example 151 (0.6 g) in THF (15 ml)was cooled to −10° C. and treated with a solution of borane in THF(1.0M, 1.5 equiv.) The reaction mixture was stirred at room temperaturefor 1 h, then re-cooled to −10° C. and treated with 4N NaOH and H₂O₂.The reaction mixture was warmed to room temperature, washed with brine,dried, filtered and evaporated. Purification by column chromatographygave the alcohol (350 mg, 56%) as a white solid. ¹H NMR (360 MHz, CDCl₃)7.37 (4H, s), 7.05-6.98 (1H, m), 6.94-6.89 (1H, m), 6.85-6.78 (1H, m),3.91-3.78 (3H, m), 3.54 (2H, t, J=5.8 Hz), 3.22-3.17 (2H, m), 2.99-2.96(2H, m), 2.01 (1H, brs), 1.84 (2H, qt, J=5.8 Hz).

Example 158

A solution of the alcohol from Example 157 (330 mg) was dissolved inCCl₄ (2 ml), MeCN (2 ml), water (3 ml) and treated with RuO₂.H₂O (5 mg)and sodium periodate (800 mg) and stirred vigorously for 1 h. Thereaction mixture was diluted with DCM, and the organic layer was dried,filtered and evaporated. Purification by column chromatography gave theacid as a solid (100 mg, 29%). ¹H NMR (400 MHz, CDCl₃) 7.37 (4H, s),7.04-6.99 (1H, m), 6.94-6.90 (1H, m), 6.84-6.78 (1H, m), 3.89 (1H, qt,J=7.4 Hz), 3.67-3.64 (2H, m), 3.23-3.18 (2H, m), 3.01-2.96 (2H, m),2.66-2.63 (2H, m).

Example 159

A solution of the acid from Example 158 was converted into thecorresponding amide in 81% yield using the conditions described inExample 154. ¹H NMR (360 MHz, CDCl₃) 7.38 (4H, s), 7.05-6.99 (1H, m),6.93-6.88 (1H, m), 6.84-6.77 (1H, m), 6.42 (1H, brs), 5.39 (1H, brs),3.95 (1H, qt, J=7.4 Hz), 3.65-3.62 (2H, m), 3.27-3.20 (2H, m), 3.05-2.99(2H, m), 2.54 (2H, t, J=5.6 Hz).

Examples 160-177

These Examples were prepared by the following method, using theappropriate amine free base or amine salt with prior neutralization.

To a stirred suspension of cis4-(4-chlorobenzenesulphonyl)-4-(2,5-difluorophenyl)cyclohexaneaceticacid (Example 50, 0.15 g, 0.35 mmol) in dichloromethane (5 ml) was addedoxalyl chloride (0.05 ml, 0.57 mmol) and dimethylformamide (1 drop).After 30 minutes the solution was evaporated to a small volume and to asolution of the residue in dichloromethane (5 ml) was added the desiredamine (1.75 mmol). After stirring the solution for 20 minutes thesolvent was removed in vacuo and the residue purified by chromatographyon silica gel eluting with increasing concentrations of ethyl acetate inisohexane (25%, 50%). The fractions containing the product wereevaporated to give the product amide. Chromatographic purification wasperformed on silica gel using appropriate concentrations of ethylacetate in isohexane, ethyl acetate or methanol in ethyl acetate whereappropriate.

Example MS m/z No. R (M + H) m.p. 160 NH-cyclobutyl 482,484 192-193° C.161 NH₂ 428,430 187-189° C. 162 NHMe 442,444 200-201° C. 163 NHEt456,458 146-147° C. 164 NH^(n)Pr 470,472 150-151° C. 165 NH^(i)Pr470,472 124-125° C. 166 NMe₂ 456,458 167 NHCH₂CH₂Ph 532,534 168 NHCH₂CF₃510,512 169

546,548 170 NHCH₂-cyclopropyl 482,484 187-188° C. 171 NH-cyclopentyl496,498 182-183° C. 172 NH-cyclopropyl 468,470 145-147° C. 173 NH^(n)Bu484,486 oil 174 NH^(t)Bu 484,486 102-110° C. 175 NHCH(Et)₂ 498,500 89-92° C. 176 NH-allyl 468,470 132-134° C. 177 NHNH^(t)Bu 499,501

Example 178

Step (1)

To a solution of the acid from Example 50 (1 g) in DCM (50 ml) and ethylacetate (30 ml) was added pentafluorophenol (1.5 equiv.) and DCC (1.5equiv.) and stirred at room temperature for 1 h. The reaction mixturewas evaporated in vacuo, taken up in ethyl acetate and filtered. Thefiltrate was evaporated in vacuo to yield the pentafluorophenol ester ofsufficient purity to use in subsequent reactions without furtherpurification.

Step (2)

To the active ester prepared in Step (1) (200 mg, 0.33 mmol) dissolvedin dry THF (3 ml) and under nitrogen was added hydrazine (1 M solutionin THF, 1.3 ml, 1.32 mmol). After 3 h the reaction was concentrateddiluted with water, extracted with ethyl acetate (×3), washed with,water, brine, dried (MgSO₄), filtered and evaporated. Purified by flashcolumn chromatography (1:1 ^(i)hexane/ethyl acetate to ethyl acetate+3%triethylamine) to give a white solid (50 mg). MS(EI+) 444 (MH+)

Example 179

A solution of the active ester from step (1) of Example 178 in DMF wastreated with acetamidoxime at room temperature. The reaction mixture wasstirred for 0.5 h, diluted with ethyl acetate, washed with water, dried,filtered and evaporated in vacuo. Purification by column chromatographygave the desired product as a white solid (180 mg, 100%). MS MH+485(487).

Example 180

A solution of the oxime from Example 179 (100 mg) in THF (5 ml) wastreated with potassium tert-butoxide solution (3 equiv.) and stirred atroom temperature for 15 mins. The reaction mixture was diluted withwater and ethyl acetate. The organic phase washed, dried, filtered andevaporated. Purification by column chromatography gave the desiredproduct (65 mg, 62%) as a white solid. MS MH+ 467(469).

Example 181

A solution of the amide from Example 161 (100 mg) was dissolved indioxane and treated with Lawesson's reagent and stirred at roomtemperature overnight. The reaction mixture was filtered and thefiltrate was evaporated in vacuo. Purification by column chromatographygave the thioamide (50 mg, 52%) as a white solid. A solution of theforegoing thioamide (40 mg) in ethanol (2 ml) was treated withchloroacetone (1.3 equiv.) and refluxed for 4 h. The reaction mixturewas evaporated in vacuo. Trituration from hexane-ethyl acetate gave thedesired product (26 mg, 59%) as a white solid. MS MH+ 482(484).

Example 182

A solution of the active ester from Example 178 step (1) in DMF wastreated with acetic hydrazide and stirred at room temperature for 15min. The reaction mixture was diluted with ether and the precipitate wascollected by filtration and washed several times with ether to give theintermediate diacyl hydrazide as a white solid. A solution of theforegoing compound (100 mg) in dioxane was treated with Lawesson'sreagent (2 equiv.) and stirred at room temperature for 1 h. The reactionmixture was evaporated in vacuo. Purification by column chromatographygave the desired product (55 mg, 52%) as a white solid. MS MH+ 483(485).

Example 183

To a solution of the cis amide from Example 128 (46 mg) and pyridine(0.053 ml) in tetrahydrofuran (1 ml) was added trifluoroacetic anhydride(0.056 ml). The solution was stirred at room temperature for 2 hourswhen 0.5M−HCl (aqueous) and ethyl acetate were added. The organic phasewas dried (MgSO₄), evaporated to a small volume and purified bychromatography on silica gel, eluting with isohexane:ethyl:acetate (5:1)to give the desired product as a colourless solid. ¹H NMR (360 MHz,CDCl₃) Λ 1.61-1.70 (2H, m), 1.86-1.94 (2H, m), 2.03-2.10 (1H, m),2.42-2.45 (4H, m), 2.51(2H, d J 8.0 Hz), 6.8 (1H, m), 7.02-7.09(2H, m),7.30 (2H, d J 8.6 Hz), 7.36(2H, d J 8.7 Hz).

Example 184

To a solution of the nitrile from Example 183 (0.43 g) indimethylformamide (0.5 ml) was added ammonium chloride (0.15 g) andsodium azide (0.15 g) and the mixture was heated at 100° C. for 12 h.0.2M−HCl (5 ml) and ethyl acetate (5 ml) were added and the organicphase washed with water (5 times) and dried (MgSO₄). The solvent wasremoved in vacuo and the residue was purified by chromatography onsilica gel (eluting with ethyl acetate, 5% methanol in ethyl acetate) togive the desired product MS m/z 451 (M−H)

Example 185

The nitrile from Example 183 (300 mg) was dissolved in methanol (3 ml)and ether (20 ml), cooled to 0° C. and treated with HCl gas for 10minutes. The reaction vessel was stoppered and left to stand at roomtemperature overnight. The reaction mixture was evaporated in vacuo togive the imidate ether hydrochloride salt (350 mg, ca 100%) as a whitesolid.

A solution of the foregoing imidate ether hydrochloride salt (100 mg) inmethanol (10 ml) was treated with acetic hydrazide (1.5 equiv.) andstirred at room temperature for 5 min. The reaction mixture wasevaporated in vacuo and taken up in Dowtherm A, treated with ammoniumchloride (100 mg) and heated at 190° C. for 2 h. The reaction mixturewas cooled and purified by column chromatography to give the desiredproduct (24 mg, 24%) as a white solid. MS MH+ 467(469).

Example 186

A suspension of the hydrazide of Example 178 (160 mg) in methanol (10ml) was treated with a solution of acetamidine (2 equiv.) in ethanol (1ml) and stirred at room temperature overnight, then refluxed for 2 h.The reaction mixture was evaporated in vacuo, dissolved inN-methylpyrrolidinone (2 ml) and xylene (30 ml) and refluxed overnightwith the azeotropic removal of water. The reaction mixture wasevaporated in vacuo, dissolved in ethyl acetate and washed with water(three times). The organic phase was dried, filtered and evaporated.Purification by column chromatography gave the desired product (137 mg,76%) as a white solid. MS MH+ 466(468).

Example 187

A solution of the triazole from Example 186 (50 mg) in DMF (1 ml) wastreated with sodium hydride (1.1 equiv.) and, after 5 minutes, methyliodide (1.5 equiv.). After 1 h, the reaction mixture was diluted withethyl acetate and water. The organic layer washed with water, dried,filtered and evaporated in vacuo. Purification by column chromatographygave the desired product (33 mg, 64%) as a white foam. ¹H NMR indicatedthis compound to be a mixture of N1/N2 methylated regioisomers. MS MH+480(482).

Example 188

A solution of the active ester from Example 178 step (1) (200 mg) intoluene was treated with a suspension of semicarbazide hydrochloride(1.1 equiv.) in DMF and triethylamine (2.2 equiv.) and stirred at roomtemperature for half an hour. The reaction mixture was diluted withether and filtered. The residue washed with ether to give the crude acylsemicarbazide as a white solid.

A suspension of this material (150 mg) in 1 M NaOH solution (20 ml) anda small amount of 1,4-dioxane was refluxed overnight. The reactionmixture was cooled and acidified with 1 M HCl. The resulting precipitatewas collected by filtration, washed with water and ether several timesand dried in vacuo to give the desired product as a white solid. MS MH+468(470).

Example 189

The hydrazide prepared in Example 178 (40 mg, 0.09 mmol) was dissolvedin triethyl orthoformate (3 ml) and heated at 150° C. for 18 h. Reactionwas concentrated and purified by flash chromatography (1:1^(i)hexane/ethyl acetate) to give a colourless glassy solid (12 mg). ¹HNMR (CDCl₃) 1.55-1.62 (2H, m), 1.77-1.82 (2H, m), 2.20-2.28 (1H, m),2.44 (1H, s), 2.50 (3H, dd, J=5.5, 14.5 Hz), 3.07 (2H, d, J=7.8 Hz),6.80-6.87 (1H, m), 7.01-7.09 (2H, m), 7.31-7.38 (4H, m), 8.36 (1H, s).

Example 190

To the acid prepared in Example 50 (1.0 g, 2.3 mmol) dissolved in THF(80 ml) under nitrogen and cooled to 0° C. were added triethylamine (0.4ml, 2.8 mmol) and isobutylchloroformate (0.36 ml, 2.8 mmol). Reactionwas stirred at 0° C. for 2 h and then the solid in the reaction mixturewas removed by filtration. The filtrate was recooled to 0° C. and sodiumborohydride (435 mg) in water (10 ml) added dropwise and the reactionwas stirred for 1 h. Reaction was concentrated, diluted with ethylacetate, washed with water, brine, dried (MgSO₄), filtered andevaporated. Purified by flash chromatography (1:1 ^(i)hexane/ethylacetate) to give the alcohol (0.96 g).

To the alcohol (400 mg, 0.97 mmol) dissolved in DCM (20 ml) was addedDess-Martin periodinane (453 mg, 1.1 mmol). Reaction stirred for 1 h andthen filtered through a pad of Celite™ and the filtrate evaporated andthe residue purified by flash chromatography (2:1 ^(i)hexane/ethylacetate) to give the aldehyde (250 mg) which was dissolved in ethanol (5ml), cooled to 0° C. and treated with glyokal (40% w/w aq solution, 0.2ml) and ammonia (25% w/w aq. solution, 1 ml). After 30 min the reactionwas allowed to warm to room temperature and stirred for 15 h. Afterconcentration the residue was diluted with brine and extracted withethyl acetate (×3). Organic extracts were dried (MgSO₄), filtered andevaporated to give the imidazole as a white solid (150 mg). ¹H NMR(CDCl₃) 1.45-1.55 (2H, m), 1.70-1.75 (2H, m), 2.17-2.22 (1H, m), 2.46(4H, dd, J=5.6, 14.0 Hz), 2.88 (2H, d, J=7.7 Hz), 6.78-6.85 (1H, m),6.98 (2H, s), 7.00-7.05 (2H, m), 7.31-7.36 (4H, M), 9.1-9.8 (1H, br).

Example 191

The imidazole prepared in Example 190 (35 mg, 0.078 mmol) was dissolvedin dry DMF (2 ml) and treated with potassium carbonate (53 mg, 0.39mmol) and iodomethane (6 μl, 0.096 mmol) and allowed to stir for 48 h.The reaction was diluted with water and extracted with ethyl acetate(×3). Organic extracts were dried (MgSO₄), filtered and evaporated andpurified by flash chromatography (ethyl acetate) to give a white solid(8 mg). ¹H NMR (CDCl₃) 1.51-1.59 (1H, m), 1.80 (4H, dd, J=3.9, 10.5 Hz),2.19-2.26 (1H, m), 2.42-2.57 (3H, m), 2.80 (2H, d, J=7.7 Hz), 3.60 (3H,s), 6.79 (1H, d, J=1.1 Hz), 6.81-6.86 (1H, m), 6.94 (1H, d, J=1.4 Hz),7.00-7.08 (2H, m), 7.34 (4H, d, J=4.2 Hz).

Example 192

The acid from Example 127 (153 mg) was dissolved in dry THF (10 ml) andcooled to 0° C. under nitrogen. Triethylamine (61 μL, 0.43 mmol) andisobutylchloroformate (57 μL, 0.43 mmol) were added and the mixturestirred at 0° C. for one hour. The precipitate that had formed wasremoved by filtration and washed with a further 5 ml of dry THF. Thecombined THF layers were recooled to 0° C. and sodium borohydride (70mg, 1.84 mmol) as a solution in water (2 ml) was added witheffervescence. After stirring for 30 minutes at 0° C., the reaction wasdiluted with ethyl acetate, washed with ammonium chloride solution,sodium bicarbonate solution and brine then dried (MgSO₄) and evaporatedto dryness. The residue was purified by column chromatography elutingwith ethyl acetate:hexane (1:3) to afford the desired alcohol (75 mg).¹H NMR (CDCl₃) 7.39-7.31 (4H, m), 7.10-7.01 (2H, m), 6.88-6.81 (1H, m),3.71 (2H, d, J=7.5 Hz), 2.46-2.32 (4H, m), 1.90-1.85 (2H, m), 1.78-1.74(1H, m) and 1.54-1.44 (2H, m). m/z=423 [MNa]⁺

Example 193

A stirred solution of the alcohol from Example 192 (294 mg, 0.74 mmol)in DCM (10 ml) was cooled to −30° C. Triethylamine (155 μl, 1.11 mmol)then methanesulfonyl chloride (68 μl, 0.89 mmol) were added and themixture stirred for 30 minutes at −30° C. The reaction was diluted withwater, warmed to ambient temperature and extracted with DCM. The organiclayer washed with citric acid solution and sodium bicarbonate solution,dried (MgSO₄) and evaporated to dryness. The residue (321 mg) could beused without further purification or purified by column chromatographyeluting with ethyl acetate:hexane (1:3) to remove small quantities ofthe trans isomer to afford the desired product. (272 mg). ¹H NMR (CDCl₃)7.36 (2H, d, J=8.5 Hz), 7.31 (2H, d, J=8.5 Hz), 7.08-7.02 (2H, m),6.87-6.83 (1H, m), 4.29 (1H, d, J=7.5 Hz), 3.05 (3H, s), 2.46-2.42 (4H,m), 2.05-2.02 (1H, m), 1.93-1.88 (2H, m) and 1.62-1.55 (2H, m). m/z=501[MNa]⁺

Example 194

To a stirred solution of the alcohol from Example 192 (59 mg, 0.15 mmol)in dry THF (5 ml) cooled to 0° C. under nitrogen was addedchlorosulfonyl isocyanate (18 μl, 0.21 mmol). The mixture was stirredfor 45 minutes at this temperature then sodium metabisulfite (84 mg,0.44 mmol) as a solution in water (1 ml) was added and stirringcontinued for 16 hours at room temperature. Ethyl acetate was added andthe mixture washed with water (×2), brine, dried (MgSO₄) and evaporatedto leave a residual solid (73 mg) which was triturated with ether andfiltered to afford the desired product (35 mg). ¹H NMR (DMSO) 7.61 (2H,d, J=8.5 Hz), 7.36 (2H, d, J=8.5 Hz), 7.35-7.30 (1H, m), 7.25-7.10 (2H,m), 6.47 (2H, br s), 3.95 (2H, d, J=7.5 Hz), 3.16 (1H, m), 2.44 (1H, m),2.23-2.14 (2H, m), 1.85-1.67 (3H, m) and 1.38-1.26 (2H, m). m/z=444[MH]⁺

Example 195

A stirred solution of 1,2,4-triazole sodium derivative (95 mg, 1.04mmol) in DMSO (5 ml) and the mesylate from Example 193 (100 mg, 0.21mmol) were heated to 100° C. for 17 hours. The reaction was cooled,diluted with dichloromethane and washed with water, brine (×2), dried(MgSO₄) and evaporated to leave a residue which was purified bypreparative thin layer chromatography eluting with ether:dichloromethane1:1 to afford the desired product. ¹H NMR (CDCl₃) 8.09 (1H, s), 7.95(1H, s), 7.36 (2H, d, J=8.5 Hz), 7.31 (2H, d, J=8.5 Hz), 7.07-7.02 (2H,m), 6.85-6.81 (1H, m), 4.27 (2H, d, J=8 Hz), 2.58-2.39 (4H, m),2.28-2.22 (1H, m), 1.75-1.68 (2H, m) and 1.6-1.48 (2H, m). m/z=452[MH]⁺.

Example 196

To a stirred solution of the alcohol from Example 192 (114 mg, 0.29mmol) in dry THF (10 ml) was added 3-hydroxypyridine (30 mg, 0.32 mmol),triphenylphosphine (164 mg, 0.63 mmol) and diethylazodicarboxylate (55μl, 0.35 mmol) and the resulting solution stirred at ambient temperaturefor 20 hours. The mixture was evaporated and purified by columnchromatography eluting with ethyl acetate:hexane (1:1) to afford thedesired product. (52 mg). ¹H NMR (CDCl₃) 8.33 (1H, s), 8.24 (1H, s),7.37-7.30 (4H, m), 7.25-7.20 (2H, m), 7.11-7.03 (2H, m), 6.88-6.82 (1H,m), 4.07 (2H, d, J=7.5 Hz), 2.50-2.43 (4H, m), 2.13-2.09 (1H, m),2.01-1.96 (2H, m) and 1.67-1.56 (2H, m). m/z=478[MH]⁺

Example 197

To a stirred solution of pyrrolidin-2-one (23 mg, 0.27 mmol) in DMF (10ml) under nitrogen was added sodium hydride (11 mg of a 60% dispersionin mineral oil, 0.27 mmol) and the mixture stirred at ambienttemperature for 20 minutes. After this time, a solution of the mesylatefrom Example 193 (44 mg, 0.09 mmol) in DMF (2 ml) was added and themixture heated to 80° C. for 4 hours. The reaction was cooled, dilutedwith ethyl acetate and washed with ammonium chloride solution, sodiumbicarbonate solution, brine, dried (MgSO₄) and evaporated to leave aresidue which was purified by preparative thin layer chromatographyeluting with ethyl acetate:hexanes 3:1 to afford the desired product (9mg).

¹H NMR (CDCl₃) 7.37 (4H, s), 7.08-7.00 (2H, m), 6.88-6.81 (1H, m),3.38-3.34 (4H, m), 2.51-2.38 (6H, m), 2.06-1.98 (2H, m), 1.92-1.87 (1H,m), 1.70-1.64 (2H, m) and 1.51-1.42 (2H, m). m/z=292[M-ArSO₂ ⁻]⁺

Using the general procedure of Example 197, and substituting theappropriate nucleophile for pyrrolidin-2-one, the following wereprepared:

Example No. NR₂ m/z 198

294 [M-ArSO₂ ⁻]⁺ 199

292 [M-ArSO₂ ⁻]⁺ 200

275 [M-ArSO₂ ⁻]⁺ 451 [MH]⁺ 201

302 [M-ArSO₂ ⁻]⁺ 478 [MH]⁺ 202

321 [M-ArSO₂ ⁻]⁺ 497 [MH]⁺ 203

307 [M-ArSO₂ ⁻]⁺ 483 [MH]⁺ 204

***  205*

452 [MH]⁺  206*

452 [MH]⁺ 207

451 [MH]⁺  208**

453 [MH]⁺  209**

453 [MH]⁺ 210

482 [MH]⁺ *obtained as a mixture using 1,2,3-triazole as nucleophile,and separated by preparative TLC (2:1 DCM/hexane 2% MeOH). **obtained asa mixture using 1,2,3,4-tetrazole as nucleophile, and separated bypreparative TLC. ***¹H NMR (CDCl₃) 7.36(4H, br s), 7.06-7.04(2H, m),6.89-6.80(1H, m), 3.64-3.62(2H, d, J=7.5Hz), 2.53-2.46(4H, m),2.04-2.01(1H, m), 1.69-1.68(2H, m) and 1.51-1.50(2H, m).

Example 211

A stirred solution of 2-hydroxypyridine (60 mg, 0.63 mmol) in DME (4 ml)and DMF (1 ml) under nitrogen was cooled to 0° C. Sodium hydride (28 mgof a 60% dispersion in mineral oil, 1.15 mmol) was then added and thesuspension stirred at 0° C. LiBr (109 mg, 1.26 mmol) was added 10minutes later. After this time, the mixture was warmed to ambienttemperature and stirred for 15 minutes. A solution of the mesylate fromExample 193 (60 mg, 0.13 mmol) in DMF (2 ml) was added and the mixtureheated to 65° C. for 18 hours. The reaction was cooled, diluted withethyl acetate and washed with ammonium chloride solution, sodiumbicarbonate solution and brine then dried (MgSO₄) and evaporated toleave a residue which was purified by preparative thin layerchromatography eluting with EtOAc:Hexane 1:5 to afford the desiredproduct (4 mg).

¹H NMR (CDCl₃) 7.55-7.30 (5H, m), 7.25-7.22 (1H, dd J=7.0, 2.0 Hz),7.09-7.00 (2H, m), 6.85-6.78 (1H, m), 6.58-6.55 (1H, d, J=9.0 Hz),6.18-6.14 (1H, m), 4.02-3.99 (2H, d, J=8.0 Hz), 2.62-2.55 (2H, m), 2.44(2H, m), 2.19-2.17 (1H, m), 1.80-1.76 (2H, m) and 1.6-1.5 (2H, m).

Example 212

To a stirred solution of the mesylate from Example 193 (90 mg, 0.19mmol) in DMF (10 ml) under nitrogen was added sodium azide (49 mg, 0.76mmol) and the mixture stirred and heated to 100° C. for 2 hours. Afterthis time, the reaction was cooled, diluted with water and extractedwith ethyl acetate (×2), the combined organic layers were washed withwater, dried (MgSO₄) and evaporated to leave a residue (76 mg) which waspurified by preparative thin layer chromatography eluting with 4%EtOAc:Hexane to afford the desired product.

¹H NMR (CDCl₃) 7.38-7.30 (4H, m), 7.09-7.01 (2H, m), 6.87-6.80 (1H, m),3.43-3.41 (2H, d, J=8.0 Hz), 2.46-2.35 (4H, m), 1.87-1.79 (3H, m),1.56-1.50 (2H, m).

Example 213

Step (1)

The alcohol from Example 192 (181 mg, 0.46 mmol) was dissolved in THFand pyridine (37 μl, 0.46 mmol) added followed by 4-nitrophenylchloroformate (103 mg, 0.51 mmol). The reaction was stirred overnight atroom temperature then the solvent removed in vacuo and the reactiontaken up in ether and washed with water (×2) and brine (×2), dried(MgSO₄) and evaporated to a foam (247 mg). Product was purified by flashcolumn chromatography (1% MeOH, 99% DCM) to yield the desired4-nitrophenylcarbonate (230 mg)

Step (2)

The carbonate (74 mg, 0.14 mmol) was dissolved in DMF (2 ml) andisopropylamine (23 μl, 0.28 mmol) added. The reaction was stirred for 10minutes then diluted with ethyl acetate and washed with 2N NaOH (×3) andbrine (×3), dried (MgSO₄) and evaporated to dryness. The crude productwas purified by prep plate (2:1 hexane:ethyl acetate) affording thedesired product (18 mg). 1H NMR (CDCl₃) 7.38-7.30 (4H, m), 7.09-6.99(2H, m), 6.88-6.79 (1H, m) 4.57-4.48 (1H, s, broad), 4.13 (2H, d, J=8.5Hz), 3.88-3.71 (1H, m), 2.49-2.38 (4H, m), 1.92-1.80 (3H, m) 1.55-1.41(2H, m), and 1.16 (6H, d, J=6.5 Hz).

Example 214

The carbonate from Example 213 step (1) (56 mg, 0.14 mmol) was dissolvedin THF (2 ml) and ethylamine (0.4 ml, 0.28 mmol, 2M solution in THF)added. The reaction was stirred for 10 minutes then evaporated to afoam. The reaction was taken up in ethyl acetate and washed with 2N NaOH(×3) and brine (×3), dried (MgSO₄) and evaporated to dryness. The crudeproduct was purified by prep plate (2:1 hexane:ethyl acetate) affordingthe desired product (18 mg). ¹H NMR (CDCl₃) 7.38-7.30 (4H, m), 7.09-6.99(2H, m), 6.88-6.79 (1H, m) 4.61-4.70 (1H, s, broad), 4.14 (2H, d, J=7Hz), 3.28-3.15 (2H, m), 2.49-2.38 (4H, m), 1.90-1.79 (3H, m) 1.55-1.42(2H, m) and 1.15 (3H, t, J=7 Hz).

Example 215

Prepared as for Example 214 using dimethylamine (2M solution in THF) asstarting material. Yield 7 mg. ¹H NMR (CDCl₃) 7.38-7.30 (4H, m),7.09-6.99 (2H, m), 6.88-6.78 (1H, m), 4.15 (2H, d, J=7 Hz), 2.91 (6H,s), 2.49-2.38 (4H, m), 1.95-1.80 (3H, m) and 1.55-1.48 (2H, m).

Example 216

Prepared as for Example 214 using cyclopropylmethylamine as startingmaterial. Yield 11 mg. ¹H NMR (CDCl₃) 7.38-7.30 (4H, m), 7.09-7.00 (2H,m), 6.88-6.78 (1H, m), 4.87-4.75 (1H, s, broad), 4.14 (2H, d, J=7 Hz),3.08-2.97 (2H, m), 2.47-2.38 (4H, m), 1.98-1.79 (3H, m), 1.55-1.41 (2H,m), 1.0-0.88 (1H, m), 0.53-0.46 (2H, m) and 0.20-0.12 (2H, m).

Example 217

Prepared as for Example 214 using methylamine (8M solution in EtOH) asstarting material. Yield 7 mg. ¹H NMR (CDCl₃) 7.38-7.30 (4H, m),7.09-7.00 (2H, m), 6.88-6.78 (1H, m), 4.68-4.56 (1H, s, broad), 4.14(2H, d, J=7 Hz), 2.81 (3H, d, J=4.89), 2.48-2.38 (4H, m), 1.91-1.76 (3H,m) and 1.56-1.41 (2H, m).

Example 218

To the pentafluorophenol ester prepared in Example 178 step (1) (140 mg,0.23 mmol) dissolved in DCM (3 ml) and under nitrogen were addedmethoxyamine hydrochloride (80 mg, 0.92 mmol) and triethylamine (0.1ml). After 1 h the reaction was concentrated, diluted with ethylacetate, washed with aq. sodium carbonate, water, brine, dried (MgSO₄),filtered and evaporated. Purified by flash column chromatography (1:1^(i)hexane/ethyl acetate to ethyl acetate/methanol) to give a whitesolid (50 mg). ¹H NMR (CDCl3) 1.56 (2H, br), 1.76 (2H, br), 2.25 (4H,br), 2.44 (4H, br), 3.78 (3H, s), 6.78-6.86 (1H, m), 7.01-7.06 (2H, m),7.29-7.37 (4H, m).

Example 219

To a stirred suspension of cis4-(4-chlorobenzenesulphonyl)-4-(2,5-difluorophenyl)cyclohexaneaceticacid (Example 50, 0.224 g, 0.52 mmol) in dichloromethane (5 ml) wasadded oxalyl chloride (0.075 ml, 0.86 mmol) and dimethylformamide (1drop). After 30 minutes the solution was evaporated to a small volumeand to a solution of the residue in dichloromethane (5 ml) was addedN,O-dimethylhydroxylamine hydrochloride (0.068 g, 0.58 mmol) anddiisopropylethylamine (0.2 ml, 1.14 mmol). After stirring the solutionfor 30 minutes the solvent was removed in vacuo and the residue purifiedby chromatography on silica gel eluting with increasing concentrationsof ethyl acetate in isohexane (33%, 50%). The fractions containing theproduct were evaporated to give the desired product as a foam. ¹H NMR(360 MHz, CDCl₃) Λ 1.50-1.56 (2H, m), 1.72-1.77 (2H, m), 2.24 (1H, m),2.44 (4H, m), 2.57 (2H, d J 7.3 Hz), 3.2 (3H, s), 3.7 (3H, s), 6.80-6.88(1H, m), 7.01-7.08 (2H, m), 7.31 (2H, dd J 6.7 Hz and 2.3 Hz), 7.36 (2H,dd J 6.7 Hz and 2.3 Hz).

Example 220

To the pentafluorophenol ester prepared in Example 178 step (1) (155 mg,0.25 mmol) dissolved in DMF (3 ml) and under nitrogen were added glycinemethyl ester hydrochloride (125 mg, 1.0 mmol) and triethylamine (0.15ml). After 2 h the reaction was diluted with water, extracted with ethylacetate (×3), washed with, water, brine, dried (MgSO₄), filtered andevaporated. Purified by flash column chromatography (1:1^(i)hexane/ethyl acetate to 9:1 ethyl acetate/methanol) to give a whitesolid (55 mg). ¹H NMR (CDCl₃) 1.08-1.16 (1H, m), 1.30-1.37 (1H, m),1.67-1.71 (1H, m), 1.75-1.79 (2H, m), 1.91-1.95 (1H, m), 2.20-2.26 (1H,m), 2.41 (4H, d, J=7.8 Hz), 3.77 (3H, s), 4.05 (2H, d, J=5.1 Hz), 6.19(1H, br), 6.79-6.85 (1H, m), 7.00-7.07 (2H, m), 7.30-7.37 (4H, m).

Example 221

The glycine ester prepared in Example 220 (50 mg, 0.1 mmol) in a sealedtube and dissolved in a 2M ammonia in methanol solution (3 ml) washeated to 50° C. for 3 h. After cooling to room temperature the reactionmixture was concentrated and purified by trituration with ether to givea white solid (28 mg). MS(EI+): 485 (MH+)

Example 222

The alcohol from Example 192 (4 g, 10 mmol) was dissolved indichloromethane (280 ml) and was treated with Dess Martin periodinane(4.66 g, 11 mmol) and the mixture was stirred for 45 mins before addingsaturated aqueous sodium bisulphite (100 ml) and after 5 mins themixture was separated and the organic phase as washed with saturatedaqueous sodium bicarbonate (100 ml) dried (MgSO₄) and evaporated todryness. The crude residue (4 g) was dissolved in dry dichloromethane(100 ml) and treated with methyl triphenylphosphinoacetate (4.7 g 14mmol), stirring at rt. for 16 hrs. The solvent was evaporated and theresidue was purified by column chromatography on silica gel eluting with10-20% ethyl acetate in hexanes, to give the product. ¹H NMR (CDCl₃)7.37-7.36 (4H, m), 7.10-7.02 (3H, m), 6.87-6.83 (1H, m), 5.91 (1H, d,J=16 Hz), 3.77 (3H, s), 2.55-2.45 (3H, m), 2.40-2.38 (2H, m), 1.95-1.90(2H,m) and 1.65-1.52 (1H, m).

Example 223

The alkene from Example 222 (3.6 g, 9 mmol) was dissolved in ethylacetate (350 ml). The flask was degassed and then 10% palladium oncarbon (400 mg) was added and the mixture stirred under an atmosphere ofhydrogen for 45 mins. The solution was filtered through Celite™ andevaporated. The clear oil obtained was purified by preparative tlceluting with 5% ethyl acetate in hexanes. The oil obtained was thenfurther purified by column chromatography on silica gel eluting with5-10% ethyl acetate in hexane to give the product. ¹H NMR (CDCl₃)7.37-7.34 (4H, m), 7.08-7.00 (2H, m), 6.85-6.81 (1H, m), 3.67 (3H, s),2.45-2.39 (4H, m), 2.33 (2H, t, J=8.4 Hz), 1.81 (2H, q, J=8.4 Hz),1.72-1.68 (2H,m) and 1.60-1.43 (3H, m).

Example 224

The ester from Example 223 (104 mg, 0.23 mmol) was dissolved in amixture of ethanol (10 ml) and water (3 ml) and stirred at 20° C. Theflask was degassed and then lithium hydroxide (27 mg, 1.15 mmol) wasadded. The mixture was stirred for 3 hrs. at room temperature. 1NHydrochloric acid was then added and the mixture washed with ethylacetate (2×50 ml). The organic phase washed with brine (50 ml), dried(MgSO₄) and evaporated. The oil obtained was then further purified bypreparative tlc eluting with ethyl acetate to give the acid. ¹H NMR(CDCl₃) 7.37-7.30 (4H, m), 7.09-6.99 (2H, m), 6.85-6.79 (1H, m),2.42-2.36 (6H, m), 1.85-1.79 (2H, m), 1.73-1.69 (2H,m), 1.63-1.58 (1H,m)and 1.53-1.45 (2H, m).

Example 225

The acid from Example 224 (52 mg, 0.118 mmol) in dichloromethane (2 ml)was treated with oxalyl chloride (88 μl, 2 M solution indichloromethane, 0.176 mmol). A drop of N,N-dimethylformamide was addedand the solution allowed to stir for 2 hours. After this time, solventwas removed in vacuo and the residue redissolved in dichloromethane (1ml). This solution was dripped into methanolic ammonia (2 M, 2 ml). Thereaction was evaporated in vacuo and the residue chromatographed onsilica, eluting with 80% ethyl acetate in hexanes. The resultingmaterial was purified further by preparative t.l.c., eluting with 100%ethyl acetate followed by recrystallisation from hot hexane to giveproduct (7.4 mg, 14%). ¹H NMR (360 MHz, CDCl₃), 1.45-1.53 (2H, m),1.57-1.65 (1H, br), 1.70-1.75 (2H, m), 1.78-1.84 (2H, m), 2.32 (2H, t,J=15.3 Hz), 2.38-2.44 (4H, br), 2.95 (3H, s), 3.02 (3H, s), 6.79-6.86(1H, m), 7.00-7.09 (2H, m), 7.31-7.37 (4H, m); ms. (ES+), 470 (M⁺1), 294(M⁺175).

Example 226

The acid from Example 224 (52 mg, 0.118 mmol) in dichloromethane (2 ml)was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (45 mg, 0.235 mmol), triethylamine (32.7 μl, 0.235 mmol)and tert-butylamine (24.6 μl, 0.235 mmol). After 2 hours stirring atroom temperature, reaction washed with hydrochloric acid (1 N, 10 ml),organics dried (MgSO₄) and evaporated in vacuo to give crude (55 mg).This material was chromatographed on silica, eluting with 20-30% ethylacetate in hexanes to give product (25 mg, 43%). ¹H NMR (400 MHz,CDCl₃), 1.35 (9H, s), 1.45-1.62 (3H, m), 1.67-1.74 (2H, m), 1.76-1.80(2H, m), 2.08-2.12 (2H, m), 2.38-2.42 (4H, br), 5.72-5.78 (1H, br),6.76-6.88 (1H, m), 7.00-7.10 (2H, m), 7.31-7.37 (4H, m).

Example 227

To a cooled (−80° C.) solution of1-(trimethylsilylethyloxymethyl)triazole (0.109 g, 0.55 mmol) intetrahydrofuran (2 ml) was added a solution of n-butyl lithium (2.5M inhexanes, 0.22 ml). The solution was stirred at −80° C. for 15 minutes,warmed to 0° C. for 5 minutes and then recooled to −80° C. To the cooledsolution was added a solution of cis4-(4-chlorobenzenesulphonyl)-4-(2,5-difluorophenyl)cyclohexaneaceticacid N,O-dimethylhydroxamate (Example 219) (217 mg, 0.46 mmol) intetrahydrofuran (3 ml). After stirring the mixture at −80° C. for 15minutes a saturated solution of aqueous ammonium chloride was added andthe product extracted with ethyl acetate. The organic phase was dried(MgSO₄), evaporated to dryness and purified by chromatography on silicagel (eluting with 25% ethyl acetate in hexane) to give the desiredproduct as a crystalline solid. MS m/z 610,612 (M+H)

Example 228

The triazole from Example 227 (0.117 g) was heated in a mixture ofethanol (10 ml) and 6M-HCl (aqueous) (5 ml) and concentrated HCl (2 ml)for 2 hours at 60° C. Water and ethyl acetate were added and the organicphase was dried (MgSO₄), evaporated in vacuo and the residue purified bychromatography on silica gel (eluting with 50% ethyl acetate in hexane,100% ethyl acetate) to give the desired product as a solid which washedwith hexane mp 147-154° C. MS m/z 480,482 (M+H). ¹H NMR (360 MHz, CD₄OD)1.51-1.60 (2H, m), 1.76 (2H, dd, J=14.3 Hz and 3.1 Hz), 2.37 (1H, m),2.5 (4H m), 3.26 (2H, d, J=7.3 Hz), 6.96 (1H, m), 7.16 (2H, m), 7.40(2H, dt, J=8.7 Hz and 2.23 Hz), 7.51 (2H, dt, J=8.7 Hz and 2.23 Hz),8.51 (1H, s).

Example 229

To a solution of the product of Example 228, (50 mg) in methanol (2 ml)was added sodium borohydride (4.5 mg 0.11 mmol). After 30 minutes ethylacetate and water were added followed by addition of solid citric acid(50 mg). The organic phase was dried (MgSO₄), evaporated to dryness andthe residue chromatographed on silica gel (eluting with ethyl acetatethen 5% methanol in ethyl acetate) to give the desired product as acolourless solid after washing the residue with hexane. MS m/z 482,484(M+H)). ¹H NMR (360 MHz, CD₄OD) 1.43-1.54 (2H, m), 1.75-1.88 (3H, m),1.54-2.0 (1H, m), 2.01-2.16 (1H,m), 2.35-2.55(5H,m), 6.93-7.00 (1H, m),7.09-7.18 (2H, m), 7.37 (2H, d, J=8.6 Hz), 7.48 (2H,d, J=8.6 Hz), 8.1(1H, v.broad s).

Example 230

The ester from Example 48 (669 mg, 1.467 mmol) in tetrahydrofuran (14ml) was cooled to −78° C., treated with sodium bis(trimethylsilyl)amide(2.20 ml, 1 M solution in tetrahydrofuran, 2.20 mmol) and stirred whilewarming to room temperature over 2 hours. Methyl iodide (457 μl, 7.36mmol) was then added to the mixture at −20° C. and stirring continued,again warming to room temperature, for 2 hours. The reaction wasquenched with glacial acetic acid (132 μl, 2.20 mmol), diluted withammonium chloride (50% aq., 80 ml) and extracted with ethyl acetate(3×100 ml). Combined organics were then washed with brine (sat., 200ml), dried (MgSO₄) and evaporated in vacuo to give crude (670 mg). Thismaterial was chromatographed on silica, eluting with 8% ethyl acetate inhexanes to give product (272 mg, 40%). ¹H NMR (400 MHz, CDCl₃), 1.16(3H, d, J=6.9 Hz), 1.28 (3H, t, J=7.1 Hz), 1.45-1.51 (2H, m), 1.71-1.77(2H, m), 1.89-1.94 (1H, m), 2.28-2.48 (3H, br), 2.54-2.60 (1H, br),2.70-2.74 (1H, m),

Example 231

A solution of α-methyl ethyl ester from Example 230 (13 mg, 0.028 mmol)in methanol/water/tetrahydrofuran (3:1:1, 1 ml) was degassed and treatedwith lithium hydroxide (3.3 mg, 0.138 mmol) and the mixture heated to90° C. After 1 hour at this temperature, the reaction was cooled to roomtemperature, acidified with hydrochloric acid (1 N, 2 ml), diluted withwater (5 ml) and extracted with ethyl acetate (3×10 ml). Combinedorganics were washed with brine (sat., 30 ml), dried (MgSO₄) andevaporated in vacuo to give crude. This material was purified bypreparative t.l.c., eluting with 3% methanol, 1% acetic acid indichloromethane to give product (7 mg, 57%). ¹H NMR (360 MHz, CDCl₃),1.22 (3H, d, J=6.9 Hz), 1.48-1.58 (2H, m), 1.74-1.96 (3H, m), 2.30-2.50(3H, br), 2.53-2.62 (1H, br), 2.71-2.81 (1H, m), 6.78-6.84 (1H, m),7.00-7.09 (2H, m), 7.30-7.37 (4H, m).

Example 232

Prepared from the ketone of Example 41, following the procedures ofExamples 47, 48 and 50. ¹H NMR (360 MHz, CDCl₃) 1.52-1.61 (2H, m),1.76-1.81 (2H, m), 2.20-2.26 (1H, m), 2.39 (2H, d, J=7.6 Hz), 2.40-2.50(4H, m), 5.37 (1H, br), 5.51 (1H, br), 6.75-6.83 (1H, m), 7.01-7.08 (2H,m), 7.51 (2H, d, J=8.3 Hz) and 7.64 (2H, d, J=8.3 Hz).

Example 233

Prepared from the acid of Example 232 by the procedure of Example 178,using ammonia in the second step. MS MH+ 462(463).

1. A compound of formula I:

wherein A is selected from: —(CH₂)_(r)—O—(CH₂)_(s)— and(—CH₂)_(r)—NR¹—(CH₂)_(s)—, wherein r and s are 0-5 such that r+s is aninteger in the range 2-5, said ring bearing, in addition to Ar² andAr¹SO₂, 0-3 substituents independently selected from ═X, halogen, CN,NO₂, N₃, R², CF₃, N(R¹)₂, OR¹, COR¹, CO₂R¹, CON(R¹)₂, OCOR¹, OCO₂R²,OCON(R¹)₂, N(R¹)COR², N(R¹)CO₂R², OSO₂R² and N(R¹)SO₂R², except that thering positions adjacent to the carbon bonded to the Ar¹SO₂ group areoccupied by unsubstituted methylene groups; X represents C(R¹)₂,CHCO₂R¹, O, S, NOR¹, CHCON(R¹)₂, NNHCOR², or the atoms necessary tocomplete a spiro-linked 5- or 6-membered carbocyclic or heterocyclicring; Ar¹ represents phenyl or pyridyl either of which bears 0-3substituents independently selected from halogen, CN, NO₂, CF₃, OH,OCF₃, C₁₋₄alkoxy or C₁₋₄alkyl which optionally bears a substituentselected from halogen, CN, NO₂, CF₃, OH and C₁₋₄alkoxy; Ar² representsphenyl, bearing 1 or 2 substituents independently selected from halogen,CN, NO₂, CF₃, OH, OCF₃, C₁₋₄alkoxy or C₁₋₄alkyl which optionally bears asubstituent selected from halogen, CN, NO₂, CF₃, OH and C₁₋₄alkoxy; R¹represents H or R², or two R¹ groups together with a nitrogen atom towhich they are mutually attached may complete an N-heterocyclyl groupbearing 0-3 substituents selected from ═O, ═S, ═NOR¹, halogen, CN, NO₂,R², CF₃, N(R^(1a))₂, OR¹, COR¹, CO₂R¹ and CON(R^(1a))₂; R^(1a)represents H or R², or two R^(1a) groups together with a nitrogen atomto which they are mutually attached may complete an N-heterocyclyl groupbearing 0-3 substituents selected from ═O, ═S, halogen, C₁₋₄alkyl CN,NO₂, CF₃, OH, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, carbamoyl, Ar and COAr; R² represents C₁₋₆alkyl,C₃₋₉cycloalkyl, C₃₋₆cycloalkylC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl orC-heterocyclyl, any of which may bear up to 3 substituents independentlyselected from halogen, CN, NO₂, N₃, CF₃, OR^(2a), N(R^(2a))₂, CO₂R^(2a),COR^(2a), OCOR^(2a), CON(R^(2a))₂, OCON(R^(2a))₂, CONR^(2a)(OR^(2a)),CONHC(═NOH)R^(2a), CON(R^(2a))N(R^(2a))₂, heterocyclyl, phenyl andheteroaryl, said heterocyclyl, phenyl and heteroaryl substituentsthemselves bearing 0-3 substituents selected from halogen, CN, NO₂, CF₃,OR^(2a), N(R^(2a))₂, CO₂R^(2a), COR^(2a), CON(R^(2a))_(2a) andC₁₋₄alkyl; or R² represents Ar; or 2 OR² groups attached to adjacentcarbon atoms may complete a 1,3-dioxolane ring; R^(2a) represents H,C₁₋₆alkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylC₁₋₆alkyl, C₂₋₆alkenyl, any ofwhich optionally bears a substituent selected from halogen, CN, NO₂,CF₃, OR^(2b), CO₂R^(2b), N(R^(2b))₂, CON(R^(2b))₂, Ar and COAr; orR^(2a) represents Ar; or two R^(2a) groups together with a nitrogen atomto which they are mutually attached may complete an N-heterocyclyl groupbearing 0-4 substituents independently selected from ═O, ═S, halogen,C₁₋₄alkyl, CN, NO₂, CF₃, OH, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, CO₂H,amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, carbamoyl, Ar and COAr;R^(2b) represents H, C₁₋₆alkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylC₁₋₆alkyl,C₂₋₆alkenyl, any of which optionally bears a substituent selected fromhalogen, CN, NO₂, CF₃, OH, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, CO₂H, amino,C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, carbamoyl, Ar and COAr; or R^(2b)represents Ar; or two R^(2b) groups together with a nitrogen atom towhich they are mutually attached may complete an N-heterocyclyl groupbearing 0-4 substituents independently selected from ═O, ═S, halogen,C₁₋₄alkyl, CN, NO₂, CF₃, OH, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, CO₂H,amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, carbamoyl, Ar and COAr; Arrepresents phenyl or heteroaryl bearing 0-3 substituents selected fromhalogen, C₁₋₄alkyl, CN, NO₂, CF₃, OH, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl,amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, carbamoyl, C₁₋₄alkylcarbamoyland di(C₁₋₄alkyl)carbamoyl; “heterocyclyl” at every occurrence thereofmeans a cyclic or polycyclic system of up to 10 ring atoms selected fromC, N, O and S, wherein none of the constituent rings is aromatic andwherein at least one ring atom is other than C; and “heteroaryl” atevery occurrence thereof means a cyclic or polycyclic system of up to 10ring atoms selected from C, N, O and S, wherein at least one of theconstituent rings is aromatic and wherein at least one ring atom of saidaromatic ring is other than C; or a pharmaceutically acceptable saltthereof.
 2. A compound according to claim 1 wherein each of r and s isat least
 1. 3. A compound according to claim 1 wherein r+s is 3 or
 4. 4.A compound according to claim 1 of formula IV, or a pharmaceuticallyacceptable salt thereof:

wherein: W represents —NR⁶—(CH₂)_(t)— or —O—CHR⁷—; R⁶ represents R¹,COR² or CO₂R²; R⁷ H or OR¹; and t is 0 or
 1. 5. A compound which isselected from the group consisting of

or a pharmaceutically acceptable salt thereof.